CN120051457A

CN120051457A - Oxalic acid amide compound, pharmaceutical composition containing oxalic acid amide compound, preparation method and application of oxalic acid amide compound

Info

Publication number: CN120051457A
Application number: CN202380073137.7A
Authority: CN
Inventors: 陈忠辉; 梅红江; 田强; 宋宏梅; 葛均友
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2022-11-15
Filing date: 2023-11-09
Publication date: 2025-05-27
Also published as: WO2024104244A1

Abstract

一种草酸酰胺化合物、包含其的药物组合物、其制备方法及其用途。具体地，一种具有式I结构的化合物，其表现出优异的PRMT5调节活性，用于预防和/或治疗与PRMT5活性相关的疾病。 An oxalamide compound, a pharmaceutical composition comprising the same, a preparation method thereof and uses thereof. Specifically, a compound having a structure of formula I, which exhibits excellent PRMT5 regulating activity, is used for preventing and/or treating diseases related to PRMT5 activity.

Description

Oxalic acid amide compound, pharmaceutical composition containing oxalic acid amide compound, preparation method and application of oxalic acid amide compound

Technical Field

The present invention relates to oxalic acid amide compounds, pharmaceutical compositions comprising the same, methods of preparing the same, and use thereof for preventing or treating diseases or conditions associated with PRMT5 activity.

Background

PRMT5 (Protein ARGININE METHYLTRANSFERASE), which is one of the members of the PRMT family (human having PRMT 1-11), catalyzes the methylation modification of arginine residues of histone and certain non-histone substrates, belongs to the epigenetic enzyme. PRMT5 is widely found in the nucleus and cytoplasm of human cells, including tissues such as heart, muscle and testis. PRMT5 belongs to type II symmetrical double methylation (sDMA) PRMT, and the methyl donor is S-adenosylmethionine (SAM) according to the different modes of catalyzing arginine methylation.

PRMT5 controls the expression degree of various target proteins through catalyzing arginine methylation of a substrate, participates in various physiological functions, and plays an important role in proliferation, metastasis and malignant transformation of tumor cells. Methylation modification of histone by PRMT5 results in silencing of oncogenes such as p53, ST7, NM23 and Rb, thereby promoting tumor development. PRMT5 regulation of non-histone proteins is mainly reflected in the effects on the localization and expression of transcription factors (NF-. Kappa.B/P65, E2F1, hoxA\GATA 4), programmed cell death protein 4 (PDCD 4), cell cycle and survival related regulatory proteins E2F1, hypoxia inducible factor 1 (HIF-1), cyclin-dependent kinases (CDKs), PI3K/Akt, etc. (Koh CM, bezzi M, guccione E.Curr Mol Bio Rep,2015,1 (1): 19-28). PRMT5 inhibits miR-99 family transcription, increases FGFR3 expression, activates Erk1/2 and Ak pathways, and causes tumor cell growth and metastasis in lung cancer cells (Pengyu Jing, nan Zhao, et al cancer Letters,2018,427,38-48). PRMT5 in colon cancer methylates Eif4e and FGFR3, promoting tumor cell growth (ZHANG B, DONG S, ZHU R, et al Oncostarget, 2015,6 (26): 22799-22811.).

MTAP is a coding gene of methylthioadenosine phosphorylase, is located on chromosome 9p21 and is close to the position of the cancer suppressor gene CDKN2A (homozygously deleted frequently), so MTAP is commonly co-deleted with CDKN2A in tumors (Marjon K, kalev P, marks K.Annual Review of Cancer Biology,2021,5 (1)), and MTAP deletion occurs in about 15% of solid tumors.

PRMT5 has 2 cofactors (cofactor), an active cofactor (SAM) and an inhibitory cofactor (MTA; 5' -methylthioadenosine), respectively. In normal cells, MTAP is responsible for converting MTA to Met (methionine) and PRMT5 is responsible for converting SAM to SAH (S-adenosyl-L-homocysteine). MTA is an endogenous competitive inhibitor of PRMT5-SAM, and in tumor cells, the deletion of MTAP causes MTA to accumulate and partially inhibit PRMT5 activity, so that the tumor cells are more dependent on PRMT5. In the above cases, inhibition of PRMT5 may further block the methylation function of PRMT5, resulting in tumor cell death.

Taken together, inhibition of PRMT5 showed synthetic lethality in the case of MTAP deletion. At present, no PRMT5 target inhibitor exists on the market. Thus, there is a need to develop new, highly potent, low toxic PRMT5 inhibitors to meet clinical needs.

Summary of The Invention

The present invention provides a novel oxalic acid amide compound which can modulate PRMT5 activity and is useful in the prevention or treatment of diseases or conditions associated with PRMT5 activity. The oxalic acid amide compound provided by the invention has good inhibition effect on MTAP-deleted tumor cells, and has good pharmacokinetic properties and the like.

One aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof:

Wherein:

ring A is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a benzo 3-8 membered cycloalkyl, a benzo 3-8 membered heterocyclyl, a 5-6 membered heteroaryl 3-8 membered cycloalkyl, a 5-6 membered heteroaryl 3-8 membered heterocyclyl, a C _3-8 cycloalkyl, a 3-8 membered heterocyclyl;

Ring B is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a 5-15 membered heteroaryl-C _6-10 aryl, a benzo 3-8 membered cycloalkyl, a benzo 3-8 membered heterocyclyl, a 5-6 membered heteroaryl-3-8 membered cycloalkyl, a 5-6 membered heteroaryl-3-8 membered heterocyclyl, a C _3-8 cycloalkyl, a 3-8 membered heterocyclyl;

R ¹ is independently at each occurrence selected from H, OH, oxo, halogen, CN, -NO ₂、-NR¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally being substituted with one or more halogens, halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl substitution;

r ² is L-R ²';

L is independently at each occurrence a direct bond or- (CR ⁵R⁶)_p -;

R ²' is independently at each occurrence selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C _3-8 Cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl 3-8 membered cycloalkyl and 5-6 membered heteroaryl 3-8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, Heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl substitution;

R ³ is selected from H, OH, halogen, CN, NR ¹⁰R¹¹、C_1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl;

r ⁴ is independently at each occurrence selected from H, OH, oxo, halogen, CN, -NO ₂、-SF₅、-NR⁷R⁸、-NHCOC_1-6 alkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl;

Or R ³ and R ⁴ together with the atoms to which they are attached form a 3-10 membered heterocyclyl;

r ⁹ is independently at each occurrence selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, said alkyl, heteroalkyl, cycloalkyl, heterocyclyl optionally substituted with one or more halo, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl;

R ⁵ and R ⁶ are each independently selected from H, OH, halogen, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally substituted with one or more halogen, OH, CN, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl, or

R ⁵ and R ⁶ form a C _3-6 cycloalkyl, 3-6 membered heterocyclyl, optionally substituted with one or more OH, halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl;

R ⁷、R⁸、R¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl, or

R ⁷ and R ⁸、R¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl optionally substituted with one or more halo, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1 or 2.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with PRMT5 activity.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a disease or condition associated with PRMT5 activity.

Another aspect of the invention provides a method of preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a process for preparing the compounds of the invention.

Detailed Description

Definition of the definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended, and do not exclude additional non-enumerated elements or method steps, although the additional non-enumerated elements or method steps do not necessarily exist (i.e., the terms also encompass the terms "consisting essentially of, and" consisting of).

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the terms "C _1-6 alkyl" and "C _1-4 alkyl" refer to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (this group is referred to herein as "haloalkyl") (e.g., CH₂F、CHF₂、CF₃、CCl₃、C₂F₅、C₂Cl₅、CH₂CF₃、CH₂Cl or-CH ₂CH₂CF₃, etc.). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C _2-6 alkenyl" as used herein refers to alkenyl groups having 2 to 6 carbon atoms and one, two, or three carbon-carbon double bonds (e.g., vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like), optionally substituted with one or more (e.g., 1-3) substituents described herein.

As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C _2-6 alkynyl" as used herein refers to an alkynyl group having 2-6 carbon atoms and one, two, or three carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), optionally substituted with one or more (e.g., 1-3) substituents as described herein.

As used herein, the term "heteroalkyl" refers to a backbone chain atom having one or more atoms independently selected from the group consisting of atoms other than carbon in the backbone carbon atom of the alkyl group, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A range of values (e.g., C _1-6 heteroalkyl) may be given to refer to the number of carbons in the chain, including 1-6 carbon atoms in this example. For example, the-CH ₂OCH₂CH₃ group is referred to as C ₃ heteroalkyl and the-CH ₂OCH₂CH₂NHCH₃ group is referred to as C ₄ heteroalkyl. The attachment to the remainder of the molecule may be through a heteroatom or carbon atom in the heteroalkyl chain.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms, and the terms "C _1-8 haloalkyl", "C _1-6 haloalkyl" and "C _1-4 haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF₃、-C₂F₅、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂Cl or-CH ₂CH₂CF₃, and the like.

As used herein, the term "hydroxyalkyl" refers to a group formed by substitution of a hydrogen atom in an alkyl group with one or more hydroxyl groups, such as C _1-4 hydroxyalkyl or C _1-3 hydroxyalkyl, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH ₃, and the like.

As used herein, the term "alkoxy" means a group inserted with an oxygen atom at any reasonable position of an alkyl group (as defined above), preferably a C _1-8 alkoxy, C _1-6 alkoxy, C _1-4 alkoxy or C _1-3 alkoxy group. Representative examples of C _1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH ₂-OCH₃, and the like, the alkoxy groups optionally being substituted with one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" as used herein means that the hydrogen atoms of the alkoxy groups are replaced with one or more (such as 1 to 3) identical or different halogen atoms.

As used herein, the term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.

As used herein, the term "spiro" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.

As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group including, but not limited to, monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like) and bicyclic alkyl groups including spiro, fused (fused) or bridged ring systems (i.e., spiro alkyl, fused (fused) alkyl, and bridged cycloalkyl groups such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and the like). In the present invention, cycloalkyl groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo (oxo) group (i.e., forming c=o). The term "C _3-8 cycloalkyl" refers to cycloalkyl having 3 to 8 ring-forming carbon atoms, such as C _3-6 cycloalkyl, which may be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and also bicycloalkyl, such as C _5-8 spirocycloalkyl, C _5-8 bridged cycloalkyl, C _5-8 fused-ring alkyl, C _5-6 spirocycloalkyl, C _5-6 bridged cycloalkyl or C _5-6 fused-ring alkyl.

As used herein, the term "cycloalkoxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic mono-or polycyclic (e.g., a parallel, spiro, or bridged) group having 2 or more (e.g., 3, 4,5,6,7, 8,9,10,11,12, 13, or 14) carbon atoms, and one or more (e.g., 1,2, 3, or 4) heteroatoms, including but not limited to oxygen, nitrogen, and sulfur atoms, the carbon atoms and heteroatoms on the heterocyclyl being optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) ₂), or optionally with one or more substituents (such as 1 to 3) independently selected from halogen and C _1-3 alkyl.

As used herein, the term "3-8 membered heterocyclyl" means a heterocyclyl containing 3-8 ring atoms including, but not limited to, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen containing heterocyclyl, 4-7 membered oxygen containing heterocyclyl, 4-7 membered sulfur containing heterocyclyl, 5-6 membered nitrogen containing heterocyclyl, 5-6 membered oxygen containing heterocyclyl, 5-6 membered sulfur containing heterocyclyl, and the like, each of which optionally also contains one or more additional heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl (e.g) Imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl).

In the present invention, the heterocyclic group may form a fused ring structure with the heterocyclic group or the cycloalkyl group, and the point of attachment of the fused ring structure to other groups may be on any heterocyclic group or cycloalkyl group, and thus, the heterocyclic group of the present invention also includes, but is not limited to, a heterocyclic-fused heterocyclic group, a heterocyclic-fused cycloalkyl group, a mono-heterocyclic-mono-heterocyclic group, a mono-heterocyclic-mono-monocycloalkyl group, for example, a 3-7-membered (mono) heterocyclic-fused 3-7-membered (mono) heterocyclic group, a 3-7-membered (mono) heterocyclic-fused (mono) cycloalkyl group, a 3-7-membered (mono) heterocyclic-fused C _4-6 (mono) cycloalkyl group, examples of which include, but are not limited to, pyrrolidinyl-fused cyclopropyl, cyclopentylazelyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl-piperidinyl, pyrrolidinyl-fused piperazinyl, piperidinyl-fused morpholinyl,

In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.

As used herein, the term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1,2,3, or 4) heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including, but not limited to, 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g. Etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally also contains one or more additional heteroatoms independently selected from oxygen, nitrogen and sulfur.

As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1,2,3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

Examples of groups resulting from the condensation of a heterocyclyl group with an aryl group include, but are not limited to: Etc.

As used herein, the term "aryl", "phenyl" or "aromatic ring" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C _6-15 aryl (aromatic ring)" means an aryl (aromatic ring) containing 6 to 15 carbon atoms, preferably a C _6-10 aryl (aromatic ring), preferably a phenyl (benzene ring) or a naphthyl (naphthalene ring). Aryl is optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO ₂、C₁-C₆ alkyl, etc.).

In the present invention, an aryl group (e.g., monoaryl) may form a fused ring structure together with a heteroaryl group (e.g., a monoheteroaryl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another aryl group (e.g., another monoaryl group) by two adjacent atoms, and the point of attachment thereof may be on any one of the aromatic rings or on other rings, including but not limited to (mono) aryl-fused (mono) heteroaryl, (mono) aryl-fused (monocycloaryl, (mono) aryl-fused (mono) heterocyclic group, and (mono) aryl-fused (mono) cycloalkyl, such as phenyl-fused 5-6 membered (mono) heteroaryl, phenyl-fused 3-8 membered (mono) heterocyclic group, or phenyl-fused C _3-8 -6 membered (mono) cycloalkyl, phenyl-fused C _4-6 (mono) cycloalkyl, examples of which include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, benzothiazole, quinolinyl, isoquinolinyl, phenyl-fused cyclobutyl, phenyl-fused cyclopentyl, phenylfused cyclohexyl Etc.

As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms, the same or different, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, for example 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) ₂).

As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaryl ring" means a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and the like. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", and "sulfur-containing heteroaryl" each optionally contain one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered bicyclic groups containing these groups, such as benzothiazolyl.

In the present invention, heteroaryl (e.g., mono-heteroaryl) may share two adjacent atoms with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclyl (e.g., mono-heterocyclyl), cycloalkyl (e.g., mono-alkyl), or another heteroaryl (e.g., another mono-heteroaryl) to form a fused ring structure, the point of attachment of which may be on any heteroaryl ring or on other rings, including, but not limited to, (mono) heteroaryl-mono-heteroaryl, (mono) heteroaryl-mono-heterocyclyl, and (mono) heteroaryl-mono-cycloalkyl, such as 5-6 membered (mono) heteroarylo 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylo phenyl, 5-6 membered (mono) heteroarylo 3-8 membered (mono) heterocyclyl, 5-6 membered (mono) heteroarylo 5-6 membered (mono) heterocyclyl, 5-6 membered (mono) heteroarylo 3-8 membered (mono) cycloalkyl or 5-6 membered (mono) heteroarylo C _4-6 (mono) cycloalkyl (such as 5-6 membered heteroarylo cyclobutyl, 5-6 membered heteroarylo cyclopentyl or 5-6 membered heteroarylo cyclohexyl), examples of which include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, benzothiazole, quinolinyl, isoquinolinyl, pyrrolopyridinyl, indolyl, isoindolyl, benzoxazolyl, quinolinyl, pyrrolopyridinyl, and the like, Etc.

As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.

The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted with one or more of", "a" is used, the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.

If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

The term "one or more" as used herein means 1 or more than 1, such as 2,3,4,5 or 10, under reasonable conditions.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (² H), Tritium (³ H)), isotopes of carbon (e.g., ¹¹C、¹³ C and ¹⁴ C), isotopes of chlorine (e.g., ³⁶ Cl), isotopes of fluorine (e.g., ¹⁸ F), isotopes of iodine (e.g., ¹²³ I and ¹²⁵ I), isotopes of nitrogen (e.g., ¹³ N and ¹⁵ N), isotopes of oxygen (e.g., ¹⁵O、¹⁷ O and ¹⁸ O), isotopes of phosphorus (e.g., ³² P), and isotopes of sulfur (e.g., ³⁵ S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). The radioisotope tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (such as ¹¹C、¹⁸F、¹⁵ O and ¹³ N) can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, acetone-D ₆ or DMSO-D ₆.

The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:

It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

Solid lines may be used hereinSolid wedge shapeOr virtual wedge shapeDepicting the chemical bond of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.

Eutectic refers to pharmaceutically active molecules bound in the same lattice with other physiologically acceptable acids, bases, salts, nonionic compounds by hydrogen bonding, pi-pi stacking, van der Waals forces, and other noncovalent bonds.

It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts:properties, selection, and Use" (Wiley-VCH, 2002).

As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in the present application, including physiologically hydrolyzable esters (compounds of the present application that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the application may themselves be esters.

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires available lone pairs to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, oxidizing heterocycles and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxirane) such as dimethyl dioxirane. These processes for the preparation of N-oxides have been described and reviewed extensively in the literature, see, for example, T.L.Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750, A.R.Katritzky and A.J.Boulton, eds., ACADEMIC PRESS, and G.W.H.Cheeseman and E.S.G.Werstiuk, ADVANCES IN Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, eds., ACADEMIC PRESS.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel DELIVERY SYSTEMS", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.

Compounds of formula (I)

In some embodiments, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof:

Wherein:

R ¹ is independently at each occurrence selected from H, OH, oxo, halogen, CN, -NO ₂、NR¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally being substituted with one or more halogens, halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl substitution;

r ² is L-R ²';

L is independently at each occurrence a direct bond or- (CR ⁵R⁶)_p -;

R ²' is independently at each occurrence selected from C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C _3-8 Cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl 3-8 membered cycloalkyl and 5-6 membered heteroaryl 3-8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, Heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl substitution;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1 or 2.

In some embodiments, each occurrence of R ⁴ is independently selected from H, OH, oxo, halogen, CN, -NO ₂、-NR⁷R⁸、-NHCOC_1-6 alkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl.

In certain embodiments, the invention provides compounds of formula I:

ring B is selected from the group consisting of C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl;

r ² is L-R ²';

L is independently at each occurrence a direct bond or- (CR ⁵R⁶)_p -;

R ²' is independently at each occurrence selected from C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-to 8-membered heterocyclyl, C _3-8 Cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogens, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl substitution;

r ⁴ is independently at each occurrence selected from H, OH, oxo, halogen, CN, -NO ₂、-NR⁷R⁸、-NHCOC_1-6 alkyl, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1 or 2.

In certain embodiments, the present invention provides compounds of formula I:

Ring a is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a benzo 3-8 membered cycloalkyl, a benzo 3-8 membered heterocyclyl, a 5-6 membered heteroaryl 3-8 membered cycloalkyl, a 5-6 membered heteroaryl 3-8 membered heterocyclyl, and a 3-8 membered heterocyclyl;

Ring B is selected from the group consisting of a 5-10 membered nitrogen containing heteroaryl ring, a 6 membered heteroaryl-heterocyclo, a 5 membered heteroaryl-heterocyclo-phenyl, a 5 membered heterocyclyl-phenyl, and a 6 membered heterocyclyl-phenyl;

R ¹ is independently at each occurrence selected from H, OH, halogen, -NR ¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _1-4 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy optionally being substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl substituted, R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form 4-6 membered heterocyclyl;

r ² is L-R ²';

L is selected from the group consisting of a direct bond, -CH ₂-、-CH(CH₃)-、-CH(CH₃)CH₂ -, -CH (cyclopropyl) -, cyclopropylene, cyclobutylene, and cyclopentylene;

R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, benzo3-8 membered cycloalkyl, benzo3-8 membered heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and cycloalkyl being optionally substituted with one or more halo, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

R ³ is selected from H, OH, halogen, -NH ₂、-NH(C_1-4 alkyl), -N (C _1-4 alkyl) ₂、C_1-4 alkyl, and C _3-6 cycloalkyl;

R ⁴ at each occurrence is independently selected from the group consisting of H, oxo, OH, halogen, CN, -NR ⁷R⁸、-NHCOCH₃、C_1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, and 3-6 membered heterocyclyl;

R ⁹ is independently at each occurrence selected from H, C _1-4 alkyl and C _3-8 cycloalkyl;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1 or 2.

In certain embodiments, the present invention provides compounds of formula I:

R ⁹ is H;

Ring a is selected from a C _6-10 aromatic ring and a 5-10 membered heteroaromatic ring;

ring B is selected from a C _6-10 aromatic ring and a 5-10 membered heteroaromatic ring;

R ¹ is independently at each occurrence selected from H, halogen, CN, -NH ₂、-CONH₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy;

r ² is L-R ²';

L is independently at each occurrence a direct bond or- (CR ⁵R⁶)_p -;

r ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkoxy, C _6-10 aryl, 5-10 membered heteroaryl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl, C _6-10 aryl, C _5-10 heteroaryl;

R ³ is selected from H and C _1-4 alkyl;

R ⁴ at each occurrence is independently selected from H, OH, halogen, CN, -NR ⁷R⁸、-NHCOCH₃、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl;

R ⁵ and R ⁶ are each independently selected from H, C _1-4 alkyl and C _3-8 cycloalkyl;

R ⁷ and R ⁸ are each independently selected from H and C _1-4 alkyl and C _3-8 cycloalkyl;

m is 0, 1,2 or 3;

n is 0, 1,2 or 3;

p is 1 or 2.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ¹ is independently selected from the group consisting of H, halogen, -NH ₂、-CONH₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-8 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ¹ is independently selected from H, -NH ₂、-CONH₂、C_1-4 alkyl, C _1-4 alkoxy.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halo, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ³ is selected from H and C _1-4 alkyl.

In certain embodiments, the invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from the group consisting of H, halogen, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ⁴ is independently selected from H, halogen, -NR ⁷R⁸、C_1-4 haloalkyl, C _1-4 haloalkoxy, 5-to 10-membered heteroaryl optionally substituted with one or more halogen, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁵ and R ⁶ are each independently selected from H, C _1-4 cycloalkyl and C _1-4 alkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁵ and R ⁶ are each independently selected from H, methyl, ethyl and cyclopropyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁵ and R ⁶ are each independently selected from H and C _1-4 alkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁵ and R ⁶ are each independently selected from H, methyl and ethyl. In certain embodiments, the present invention provides compounds of formula I wherein R ⁷ and R ⁸ are each independently selected from H and C _1-4 alkyl.

In certain embodiments, the present invention provides compounds of formula I wherein m is 0, 1 or 2.

In certain embodiments, the present invention provides compounds of formula I wherein n is 0, 1 or 2.

In certain embodiments, the present invention provides compounds of formula I wherein p is 1.

In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from the group consisting of C _6-15 aromatic rings and 5-15 membered heteroaromatic rings.

In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from the group consisting of C _6-10 aromatic rings and 5-10 membered heteroaromatic rings.

In certain embodiments, the present invention provides compounds of formula I wherein ring a is selected from 5-10 membered nitrogen containing heteroaryl rings.

In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,Preferably, ring A is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,

In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from the group consisting of pyridinyl, Preferably, ring A is selected from the group consisting of pyridinyl,

In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from Preferably, ring A is selected from

In certain embodiments, the present invention provides compounds of formula I,Selected from the group consisting of Preferably, the method comprises the steps of,Selected from the group consisting of

In certain embodiments, the present invention provides compounds of formula I,Selected from the group consisting of

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a 5-15 membered heteroarylphenyl group, and a benzo 3-8 membered heterocyclyl group.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, and a 3-8 membered heterocycloalkylphenyl.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a C _6-10 aromatic ring, a 5-to 10-membered heteroaromatic ring, a 5-to 6-membered heteroarylphenyl group, and a 5-to 6-membered heterocyclylphenyl group.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of C _6-10 aromatic rings and 5-10 membered heteroaromatic rings and 5-6 membered heterocycloalkylphenyl.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of 5-10 membered nitrogen containing heteroaryl ring, 6 membered heteroaryl-heterocyclyl, 5 membered heteroaryl-phenyl, 5 membered heterocyclyl-phenyl, and 6 membered heterocyclyl-phenyl.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of 5-10 membered nitrogen containing heteroaryl rings and 6 membered heterocycloalkylphenyl.

In certain embodiments, the present invention provides compounds of formula I, ring B is selected from benzene ring, naphthalene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, indole ring, isoindole ring, indazole ring, benzimidazole ring, benzothiazole ring, quinoline ring, isoquinoline ring,A benzopiperidine ring, a benzopetrahydrofuran ring and a pyridopyran ring.

In certain embodiments, the present invention provides compounds of formula I, ring B is selected from benzene ring, naphthalene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, indole ring, isoindole ring, indazole ring, benzimidazole ring, benzothiazole ring, quinoline ring, isoquinoline ring,

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a benzene ring, a pyridine ring, a pyridazine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a benzopiperidine ring,A benzotetrahydrofuran ring and a pyridopyran ring.

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a benzene ring, a pyridine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring,

In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from the group consisting of a benzene ring,

In certain embodiments, the present invention provides compounds of formula I wherein R ¹ is independently at each occurrence selected from H, OH, halogen, NR ¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, 3-8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy optionally being substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl substituted, R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form 4-6 membered heterocyclyl.

In certain embodiments, the invention provides compounds of formula I wherein R ¹ is independently selected at each occurrence from H, OH, halogen, NR ¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl optionally substituted with one or more halogen, OH, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ¹ is independently selected at each occurrence from H, OH, halogen, NR ¹⁰R¹¹、-CONR¹⁰R¹¹、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, R ¹⁰ and R ¹¹ are independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, the invention provides compounds of formula I wherein each occurrence of R ¹ is independently selected from H, halogen, -NHC _1-4 alkyl, -N (C _1-4 alkyl) ₂, azetidinyl, pyrrolidinyl, piperidinyl, -NH ₂、-CONH₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-8 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ¹ is independently selected from the group consisting of H, -CH ₃、-NH₂、-OCH₃, and-CONH ₂.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ¹ is independently selected from H, -CH ₃、-NH₂、-OCH₃.

In certain embodiments, the invention provides compounds of formula I wherein L is selected from the group consisting of a direct bond, -CH (C _1-6 alkyl) -, C _3-6 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein L is selected from the group consisting of a direct bond, -CH ₂-、-CH(CH₃)-、-CH(CH₃)CH₂ -, -CH (cyclopropyl) -, cyclopropylene, cyclobutylene, and cyclopentylene.

In certain embodiments, the invention provides compounds of formula I wherein L is selected from the group consisting of direct bond, -CH (CH ₃) -, -CH (cyclopropyl) -, cyclopropyl, cyclobutyl, cyclopentyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, benzo3-8 membered cycloalkyl, benzo3-8 membered heterocyclyl, 5-6 membered heteroaryl-3-8 membered cycloalkyl, 5-6 membered heteroaryl-5-6 membered heteroaryl, 5-6 membered heteroaryl-3-8 membered heterocyclyl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and cycloalkyl being optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl, C _6-10 heteroaryl, 5-10 membered heteroaryl.

In certain embodiments, the present invention provides compounds of formula I wherein each R ²' is independently selected at each occurrence from C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, benzo3-8 membered cycloalkyl, benzo3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and cycloalkyl being optionally substituted with one or more halogen, OH, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃-₆ heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylheteroaryl, heteroaryl and cycloalkyl being optionally substituted with one or more halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylcycloalkyl optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylheteroaryl, heteroaryl and cycloalkyl being optionally substituted with one or more halo, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylcycloalkyl being optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH ₂OCH₃, morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl,The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridinyl, and,Optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, -CH ₂OCH₃, morpholinyl, pyrazolyl, pyridinyl, The methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, morpholinyl, pyrazolyl, pyridinyl, and,Optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy groups.

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl,-CH₂OCH₃、

In certain embodiments, the present invention provides compounds of formula I wherein R ²' is independently at each occurrence selected from the group consisting of methyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl,-CH₂OCH₃、

In certain embodiments, the present invention provides compounds of formula I wherein R ² is independently at each occurrence selected from the group consisting of methyl, isopropyl, trifluoroethyl, isobutyl,

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ² is independently selected from

In certain embodiments, the present invention provides compounds of formula I wherein R ³ is selected from H, OH, halogen, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, and C _3-6 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ³ is selected from H and methyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently selected at each occurrence from the group consisting of H, oxo, OH, halogen, CN, -NR ⁷R⁸、-NHCOCH₃、C_1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, and 3-6 membered heterocyclyl.

In certain embodiments, the invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from H, OH, halogen, CN, -NR ⁷R⁸、-NHCOCH₃、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently selected at each occurrence from the group consisting of H, oxo, OH, halogen, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl optionally substituted with one or more halogens, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, and 3-6 membered heterocyclyl.

In certain embodiments, the invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from H, OH, halogen, CN, -NR ⁷R⁸、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from the group consisting of H, oxo, CN, halogen, -NR ⁷R⁸、C_1-4 haloalkyl, 3-8 heterocyclyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl being optionally substituted with one or more halogen, -NR ⁵R⁶、C_1-4 alkyl, and C _1-4 haloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently selected at each occurrence from the group consisting of H, oxo, CN, F, -NH ₂、-NH(C_1-4 alkyl), -N (C _1-4 alkyl) ₂, azetidinyl, pyrrolidinyl, piperidinyl, CF ₃、C_3-8 cycloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, and 5-6 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl being optionally substituted with one or more halo, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from H, F, -NH ₂、-NH(C_1-4 alkyl), -N (C _1-4 alkyl) ₂, azetidinyl, pyrrolidinyl, piperidinyl, CF ₃, 5-6 membered heteroaryl optionally substituted with one or more halo, -NR ⁵R⁶、C_1-4 alkyl, C _1-4 haloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently at each occurrence selected from H, oxo, F, -N (CH ₃)₂、CF₃),CN, cyclopropyl,-SF ₅ and-OCF ₃.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁴ is independently selected from H, F, -N (CH ₃)₂、CF₃),

In certain embodiments, the present invention provides compounds of formula I wherein R ³ and R ⁴ together with the atoms to which they are attached form a 3-8 membered heterocyclyl, e.g., a 3-6 membered oxygen containing heterocyclyl, e.g., a 5 membered oxygen containing heterocyclyl and a 6 membered oxygen containing heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, and C _3-8 cycloalkyl, optionally substituted with one or more halogen, OH, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, or R ⁵ and R ⁶ form a C _3-6 cycloalkyl, 3-6 membered heterocyclyl with the carbon atom to which they are attached, optionally substituted with one or more halogen, OH, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, the compounds of formula I provided herein, R ⁵ and R ⁶ are each independently selected from H, C _1-4 alkyl, or R ⁵ and R ⁶ form cyclopropyl, cyclobutyl, cyclopentyl with the carbon atom to which they are attached.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁷ and R ⁸ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, optionally substituted with one or more halogen, CN, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl, or

R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with one or more halo, CN, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁷ and R ⁸ are each independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁷ and R ⁸ are each independently selected from H and C _1-4 alkyl.

In certain embodiments, the invention provides compounds of formula I wherein each R ⁹ at each occurrence is independently selected from H, C _1-6 alkyl C _3-8 cycloalkyl, 3-8 membered heterocyclyl, optionally substituted with one or more halo, OH, CN, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C ₃-₆ heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I wherein each occurrence of R ⁹ is independently selected from H, C _1-4 alkyl, C _3-8 cycloalkyl.

In certain embodiments, the invention provides compounds of formula I wherein R ⁹ is H.

In certain embodiments, the present invention provides compounds of formula I wherein R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl optionally being substituted with one or more halo, CN, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-to 6-membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 3-to 8-membered heterocyclyl, optionally substituted with one or more halogen, amino, or amino, CN, -NH ₂、NH(C_1-4 alkyl), N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl substituents.

In certain embodiments, the present invention provides compounds of formula I wherein R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ¹⁰ and R ¹¹ are each independently selected from H, C _1-4 alkyl.

In certain embodiments, the present invention provides compounds of formula I wherein m is 1 or 2, e.g., m is 2.

In certain embodiments, the present invention provides compounds of formula I wherein n is 1 or 2, e.g., n is 1.

In certain embodiments, the present invention provides compounds of formula I as compounds of formula I-1:

Wherein:

Ring A, ring B, R ¹、R²、R⁴、R⁹, m, n are as defined above for the compounds of formula I, and

Q is 0 or 1.

In all of the above embodiments, the wavy lineRepresenting the point of attachment of the group to the remainder of the molecule.

Those skilled in the art will appreciate that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of technical features or preferred technical features of one embodiment with technical features or preferred technical features of another embodiment are also included within the scope of the present invention.

In some embodiments, compounds of the invention include, but are not limited to:

Preparation method

The compounds of the present invention may be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers and diastereomers may be separated or resolved by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis (see, e.g. selective crystallization techniques or chiral chromatography(See for example,J.Jacques,et al.,"Enantiomers,Racemates,and Resolutions",John Wiley and Sons,Inc.,1981,and E.L.Eliel and S.H.Wilen).

In certain embodiments, the present invention provides a process for preparing a compound of formula I comprising the steps of:

The first step is that the compound I-A-1 and R ²NH₂ are subjected to reductive amination reaction to generate a compound I-A-2;

The second step is that the compound I-A-3 and acyl chloride The compound I-A-4 is produced through condensation reaction;

thirdly, the compound I-A-4 is subjected to hydrolysis reaction to generate a compound I-A-5;

Fourthly, performing condensation reaction on the compound I-A-2 and the compound I-A-5 to generate a compound I;

If necessary, carrying out a fifth step, namely removing protecting groups from the condensation product of the fourth step to obtain a compound I,

Wherein ring a, ring B, R ¹、R²、R³、R⁴、R⁹, m, n are as defined above.

In some embodiments of the present invention, the reductive amination reaction in the first step described above is preferably performed in the presence of Ti (OiPr) ₄ and NaBH ₄,Ti(OiPr)₄ and NaBH (OAc) ₃, or AcOH and NaBH (OAc) ₃, etc., and solvents such as THF, dichloromethane (DCM) or Dichloroethane (DCE) may be used.

In some embodiments of the invention, the condensation reaction in the second step described above is carried out in the presence of a base, preferably triethylamine or diisopropylethylamine, and a solvent such as THF may be used.

In some embodiments of the invention, the hydrolysis reaction in the third step is carried out in an aqueous solution of a base, preferably in an aqueous solution of a base such as LiOH, naOH, etc., and a solvent such as THF, methanol or ethanol may be used.

In some embodiments of the invention, the condensation reaction in the fourth step described above is carried out in the presence of a condensing agent, preferably in the presence of one or more of the condensing agents HATU, pyBOP, T ₃ P, EDCI, pyBrOP, etc., a useful base such as triethylamine or diisopropylethylamine, and a useful solvent such as DMF or NMP.

In some embodiments of the present invention, the protecting group removal reaction in the fifth step is preferably performed under the action of an acid.

In some embodiments of the present invention, the deprotection reaction in the fifth step is preferably performed under the action of an acid such as aqueous hydrochloric acid, hydrochloric acid-ethyl acetate solution, hydrochloric acid-1, 4-dioxane solution or trifluoroacetic acid.

In some embodiments of the present invention, the protecting group removed in the fifth step is preferably an amino protecting group.

In some embodiments of the present invention, the protecting group removed in the fifth step is preferably a protecting group such as t-butoxycarbonyl or 3, 4-dimethoxybenzyl.

It will be appreciated by those skilled in the art that depending on the desired product structure, one or more of the steps in the above-described preparation methods may be omitted, and the order of the reaction steps may be appropriately adjusted as desired, as well as the addition or omission of protection/deprotection reaction steps.

Pharmaceutical compositions, formulations and methods of treatment

In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

In some embodiments, the present invention provides a pharmaceutical formulation, preferably a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more other therapeutic agents.

In some embodiments, the pharmaceutical composition or pharmaceutical formulation is preferably administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route.

In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with PRMT5 activity.

In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for modulating (e.g., reducing or inhibiting) PRMT5 activity.

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, for use in the prevention or treatment of a disease or condition associated with PRMT5 activity.

In some embodiments, the invention provides a method of preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic label, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention.

In some embodiments, the disease or condition associated with PRMT5 activity is cancer or tumor.

In some embodiments, the disease or condition associated with PRMT5 activity is preferably an MTAP-deleted cancer or tumor.

In some embodiments, the cancer or tumor is preferably esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL), lymphoma, and the like.

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg per kg body weight per day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

The compounds of the present invention may be present in the pharmaceutical composition or pharmaceutical formulation in an amount or amount of about 0.01mg to about 1000mg.

As used herein, unless otherwise indicated, the term "preventing" refers to the prior administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or disorder. Those of ordinary skill in the medical arts recognize that the term "preventing" is not an absolute term. In the medical field, it is understood that prophylactic administration of a drug to substantially reduce the likelihood or severity of a disorder or symptoms of a disorder is intended in the meaning of the present disclosure. Physician's desk reference (Physician' S DESK REFERENCE), standard text in the field, uses the term "prevent" hundreds of times. As used herein, the term "preventing" with respect to a disorder or disease refers to avoiding the cause, effect, symptom, or progression of the disease or disorder before the disease or disorder is fully manifested.

The term "treating" means reversing, alleviating, inhibiting the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other agents useful in the treatment of cancer or neoplastic disease). In some embodiments, the methods of treatment of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other agents useful in treating cancer or neoplastic disease).

Detailed Description

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

Abbreviations used herein have the following meanings:

The compounds of the invention are isolated and purified by preparative TLC, silica gel column chromatography, prep-HPLC and/or Flash column chromatography (Flash column chromatography), the structure of which is confirmed by ¹ H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.

¹ H NMR spectroscopy used a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD MHz).

LC/MS employed Aglient 1260 Infinity/Aglient 6120 Quadrupole.

TLC uses silica gel GF 254 as the stationary phase.

Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as a stationary phase.

Flash column chromatography using a Biotage flash column chromatograph.

Prep-HPLC employed Agilent type 1260 and Waters 2489.

The microwave reaction was performed using a BiotageInitiator microwave reactor.

In the examples below, the temperature of the reaction was room temperature (15-30 ℃) unless otherwise specified.

The reagents used in the present application are available from Acros Organics, ALDRICH CHEMICAL Company, or Tebert chemistry, among others.

Synthetic examples:

Intermediate Int-A:2- ((6- ((tert-butoxycarbonyl) amino) -5-methylpyridin-3-yl) amino) -2-oxoacetic acid

First step Synthesis of tert-butyl (3-methyl-5-nitropyridin-2-yl) carbamate (Compound Int A-2)

Int A-1 (5 g,32.65 mmol) and (Boc) ₂ O (7.84 g,35.92 mmol) were added to DMF (50 mL) and NaH (1.44 g,35.92 mmol) was added slowly and stirred for 16hr at 25 ℃. After the reaction, quench the reaction mixture with water, extract with ethyl acetate (50 ml x 3), combine the organic phases, wash the organic phases with clear water, saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to dryness to get crude product. The crude product was purified by column chromatography on silica gel (DCM: meoh=5:95) to give compound Int a-2 (2.5 g). MS (ESI, m/z): 254.1[ M+H ] ⁺.

Second step Synthesis of tert-butyl (5-amino-3-methylpyridin-2-yl) carbamate (Compound Int A-3)

Int A-2 (2.8 g,11.06 mmol) was dissolved in MeOH (100 mL), replaced with hydrogen, and stirred at 25℃under hydrogen balloon pressure for 2hr. After the reaction was completed, the reaction mixture was filtered through celite, and the cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give Compound Int A-3 (2.45 g). MS (ESI, m/z): 224.2[ M+H ] ⁺.

Third step Synthesis of ethyl 2- ((6- ((tert-Butoxycarbonyl) amino) -5-methylpyridin-3-yl) amino) -2-oxoacetate (Compound Int A-4)

Int A-3 (2.47 g,11.06 mmol) and DIPEA (2.14 g,16.59 mmol) were dissolved in THF (50 mL) and oxalyl chloride monoethyl ester (1.66 g,12.17 mmol) was slowly added and stirred at 25℃for 0.5hr after addition. After the reaction, quench the reaction mixture with water, extract with ethyl acetate (50 ml x 3), combine the organic phases, wash the organic phases with clear water, saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to dryness to get crude product. The crude product was purified by column chromatography on silica gel (EA: pe=35:65) to give compound Int a-4 (2.7 g). MS (ESI, m/z): 324.1[ M+H ] ⁺.

Fourth step Synthesis of 2- ((6- ((tert-Butoxycarbonyl) amino) -5-methylpyridin-3-yl) amino) -2-oxoacetic acid (Compound Int A)

Int A-4 (100 mg, 309.27. Mu. Mol) and LiOH. H ₂ O (26 mg, 618.54. Mu. Mol) were added to THF (5 mL) and H ₂ O (1 mL), and stirred at 25℃for 2hr. After the completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to remove the solvent, whereby Compound Int A (90 mg) was obtained. MS (ESI, m/z): 296.1[ M+H ] ⁺.

Intermediates Int B and Int C (R) -1- (pyrimidin-2-yl) ethane-1-amine (Int B) and (R) 1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethane-1-amine (Int C)

First step (R) -2-methyl-N- (1- (pyrimidin-2-yl) ethylene) propane-2-sulfinamide (compound Int B-3) Synthesis

Int B-1 (1 g,8.19 mmol) and Int B-2 (1.78 g,9.83 mmol) were dissolved in anhydrous THF (20 mL), ti (iPrO) 4 (4.65 g,16.38mmol,4.85 mL) was slowly added, and the temperature was raised to 75℃after the addition to react for 12hr. After the reaction was completed, the reaction was cooled to room temperature to give Compound Int B-3 (1.8 g), which was directly taken to the next step. MS (ESI, m/z): 226.1[ M+H ] ⁺.

Second step Synthesis of (R) -2-methyl-N- ((R) -1- (pyrimidin-2-yl) ethyl) propane-2-sulfinamide (Compound Int B-4)

NaBH ₄ (604.49 mg,15.98 mmol) was added to the reaction flask of the previous step Int B-3 (1.8 g,7.99 mmol) at 25deg.C, the reaction was continued at 25deg.C for 2hr, after completion of the reaction, a proper amount of water was added to quench the reaction, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meOH=93:7) to give Compound Int B-4 (1.5 g). MS (ESI, m/z): 228.1[ M+H ] ⁺.

Third step (R) -1- (pyrimidin-2-yl) ethane-1-amine (Compound Int B) Synthesis

Int B-4 (1.5 g,6.60 mmol) was dissolved in MeOH (15 mL), then 4N HCl-1, 4-dioxane (5 mL) was slowly added, the reaction system was reacted at 25℃for 1hr, after completion of the reaction, concentrated under reduced pressure, then dissolved in a suitable amount of methanol, and several drops of triethylamine were added to adjust the pH to 7-8, and concentrated under reduced pressure to give Compound Int B (800 mg). MS (ESI, m/z): 124.1[ M+H ] ⁺.

Fourth step (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (Int C) Synthesis

Int B (600 mg,1.46 mmol) and Int C-1 (255.93 mg,1.46 mmol) were dissolved in anhydrous DCM (20 mL) and AcOH (175.53 mg,2.92 mmol) was added and the resulting mixture stirred at 25℃for 30min. NaBH (OAc) ₃ (464.65 mg,2.19 mmol) was then added and after the addition was complete the reaction was continued at 25℃for 1.5hr. After completion of the reaction, the reaction was quenched with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=92:8) to give compound Int C (230 mg). MS (ESI, m/z): 283.1[ M+H ] ⁺.

Intermediate Int D (5- (trifluoromethyl) pyridin-2-yl) methylamine

To the autoclave were added Int D-1 (2.00 g,11.62 mmol), palladium on carbon (0.2 g), acOH (697.82 mg,11.62 mmol) and methanol (5 mL), and the mixture was reacted at 25℃under a pressure of 1MPa for 16hr after hydrogen substitution. After the reaction was completed, the filtrate was concentrated by suction filtration through celite pad. The crude product was dissolved in ethyl acetate and added with an equal volume of water, the organic layer was discarded after separation by extraction, and the aqueous layer was lyophilized to give compound Int D (724 mg). MS (ESI, m/z): 177.1[ M+H ] ⁺.

Intermediate Int E2- ((7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) amino) -2-oxoacetic acid

First step Synthesis of 4-bromo-7-chloro-1-methyl-1H-pyrazolo [3,4-c ] pyridine (Compound Int E-2)

Int E-1 (5 g,21.51 mmol) was dissolved in DMF (30 mL) and NaH (1.72 g,43.02 mmol) was slowly added under ice bath and reacted for 30min after addition was complete, then MeI (3.66 g,25.81 mmol) was added and stirring was continued at 25℃for 2hr after addition was complete. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (50 ml×3), the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE: ea=70:30) to give compound Int E-2 (3.0 g). MS (ESI, m/z): 245.9[ M+H ] ⁺.

Second step Synthesis of 4-bromo-N- (2, 4-dimethoxybenzyl) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-7-amine (Compound Int E-4)

Int E-2 (3.0 g,12.17 mmol), int E-3 (3.05 g,18.26 mmol) and DIPEA (2.36 g,18.26mmol,3.2 mL) were dissolved in NMP (10 mL), and after nitrogen substitution, stirred at 140℃for 5hr. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (50 ml×3), the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography on silica gel (PE: EA=70:30) gave compound Int A-4 (4.0 g). MS (ESI, m/z): 377.0[ M+H ] ⁺.

Third step Synthesis of N- (2, 4-dimethoxybenzyl) -4- ((diphenylmethylene) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-7-amine (Compound Int E-6)

Int E-4(4.0g,10.60mmol)、Int E-5(3.84g,21.21mmol)、^tBuONa(3.06g,31.81mmol)、BINAP(660mg,1.06mmol) And Pd ₂(dba)₃ (4815 mg,0.53 mmol) were dissolved in toluene (10 mL) and after nitrogen substitution, the reaction temperature was raised to 80℃and stirred for 16hr. After the reaction is finished, concentrating under reduced pressure until the reaction is dried to obtain a crude product. The crude product was purified by column chromatography on silica gel (EA: pe=90:10) to give compound Int a-6 (4.68 g). MS (ESI, m/z): 478.2[ M+H ] ⁺.

Fourth step, synthesis of N ⁷ - (2, 4-dimethoxybenzyl) -1-methyl-1H-pyrazolo [3,4-c ] pyridine-4, 7-diamine (Compound Int E-7)

Int E-6 (4.68 g,9.80 mmol) was dissolved in MeOH (30 mL), then 4N hydrochloric acid-1, 4-dioxane (3 mL) was added, and after replacing nitrogen, the reaction was stirred at 30℃for 1hr. After the reaction is finished, concentrating under reduced pressure until the reaction is dried to obtain a crude product. The crude product was purified by column chromatography on silica gel (DCM: meoh=90:10) to give compound Int E-7 (3 g). MS (ESI, m/z): 314.1[ M+H ] ⁺.

Fifth step Synthesis of ethyl 2- ((7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) amino) -2-oxoacetate (Compound Int E-8)

Int E-7 (3 g,9.57 mmol) and DIPEA (3.71 g,28.72 mmol) were dissolved in THF (25 mL) and oxalyl chloride monoethyl ester (1.57 g,11.49 mmol) was slowly added and stirred at 25℃for 0.5hr after addition. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (50 ml×3), the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (EA: pe=50:50) to give compound Int E-8 (1.38 g). MS (ESI, m/z): 414.1[ M+H ] ⁺.

Sixth step Synthesis of 2- ((7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) amino) -2-oxoacetic acid (Compound Int E)

Int E-8 (1.38 g,3.34 mmol) and LiOH. H ₂ O (280 mg,6.68 mmol) were added to THF (15 mL) and H ₂ O (3 mL) and stirred at 25℃for 2hr. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to remove the solvent, whereby Compound Int E (1 g) was obtained. MS (ESI, m/z): 386.1[ M+H ] ⁺.

Intermediate Int F2- ((4- ((4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [4,3-c ] pyridin-7-yl) amino) -2-oxoacetic acid

First step, synthesis of 2-amino-5-bromo-4-chloronicotinaldehyde (Compound Int F-2)

Int F-1 (1 g,6.39 mmol) was dissolved in anhydrous DCE (20 mL), NBS (1.25 g,7.03 mmol) was added, and the mixture was warmed to 60℃for 2hr after N ₂ was protected. After the reaction was completed, the solvent was removed by concentration under reduced pressure, dissolved in water, extracted with ethyl acetate, and the organic layer was dried and concentrated to give intermediate Int F-2 (1.4 g).

Second step Synthesis of 7-bromo-1-methyl-1H-pyrazolo [4,3-c ] pyridin-4-amine (Compound Int F-4)

Int F-2 (1.5 g,6.37 mmol) and methylhydrazine sulfate (1.38 g,9.56 mmol) were dissolved in EtOH (30 mL), DIPEA (4.12 g,31.85 mmol) was added, and after N ₂ protection, the temperature was raised to 80℃for reaction for 24hr. After completion of the reaction, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: meoh=80:20) to give intermediate Int F-4 (320 mg). MS (ESI, m/z): 226.9[ M+H ] ⁺.

Third step, 7-bromo-N- (4-methoxybenzyl) -1-methyl-1H-pyrazolo [4,3-c ] pyridin-4-amine (Compound Int F-5)

Int F-4 (280 mg,1.23 mmol) and DIPEA (318.74 mg,2.47 mmol) were dissolved in anhydrous NMP (10 mL), PMBCl (289.68 mg,1.85 mmol) was added, and after protection with N ₂, the temperature was raised to 140℃for reaction for 5hr. After the reaction, water is added for dilution, ethyl acetate is used for extraction, saturated brine is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, and the crude product is separated and purified by normal phase Flash (PE: EA=92:8) to obtain an intermediate Int F-5 (150 mg). MS (ESI, m/z): 347.0[ M+H ] ⁺.

Fourth step Synthesis of 7- ((diphenylmethylene) amino) -N- (4-methoxybenzyl) -1-methyl-1H-pyrazolo [4,3-c ] pyridin-4-amine (Compound Int F-6)

Int F-5(200mg,576.02μmol)、Int E-5(208.79mg,1.15mmol)、t-BuONa(166.07mg,1.73mmol)、BINAP(35.87mg,57.60μmol) And Pd ₂(dba)₃ (26.37 mg, 28.80. Mu. Mol) were dissolved in toluene (10 mL), and the mixture was reacted at 80℃for 16hr after N2 protection. After the reaction, toluene was removed by concentration under reduced pressure, and the crude product was purified by normal phase Flash (PE: EA=79:21) to give intermediate Int F-6 (80 mg). MS (ESI, m/z): 448.2[ M+H ] ⁺.

Fifth step, N ⁴ - (4-methoxybenzyl) -1-methyl-1H-pyrazolo [4,3-c ] pyridine-4, 7-diamine (Compound Int F-7)

Int F-6 (80 mg, 178.76. Mu. Mol) was dissolved in methanol (3 mL), 4N HCl-dioxane (0.3 mL) was added dropwise, and the reaction system was reacted at 25℃for 1hr. After the reaction was completed, the solvent was removed by concentrating under reduced pressure, then an appropriate amount of methanol was added to dissolve, then several drops of TEA were added to adjust the pH to 7-8, concentrating under reduced pressure, and the crude product was isolated and purified by normal phase Flash (DCM: meoh=93:7) to obtain intermediate Int F-7 (50 mg). MS (ESI, m/z): 284.1[ M+H ] ⁺.

Sixth step Synthesis of ethyl 2- ((4- ((4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-7-yl) amino) -2-oxoacetate (Compound Int F-8)

Int F-7 (90 mg, 317.65. Mu. Mol), DIPEA (41.05 mg, 317.65. Mu. Mol) were dissolved in THF (10 mL), and oxalyl chloride monoethyl ester (52.04 mg, 381.18. Mu. Mol) was slowly added thereto, and the reaction system was reacted at 25℃for 1hr. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the crude product was isolated and purified by normal phase Flash (DCM: meoh=90:10) to give intermediate Int F-8 (110 mg). MS (ESI, m/z): 384.2[ M+H ] ⁺.

Seventh step Synthesis of 2- ((4- ((4-methoxybenzyl) amino) -1-methyl-1H-pyrazolo [4,3-c ] pyridin-7-yl) amino) -2-oxoacetic acid (Compound Int F)

Int F-8 (120 mg, 312.99. Mu. Mol) was dissolved in THF (5 mL) and H ₂ O (1 mL), naOH (25.04 mg, 625.98. Mu. Mol) was added thereto, and the reaction system was warmed to 90℃for 2hr. After completion of the reaction, the solvent was removed by concentration under reduced pressure to give intermediate Int F (115 mg). MS (ESI, m/z): 356.1[ M+H ] ⁺.

Intermediate Int G (S) -N-methyl-6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-amine hydrochloride

First step Synthesis of tert-butyl (S) - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) carbamate (Compound Int G-2)

The hydrochloride salt of Int G-1 (2.0G, 8.35 mmol) was added to DCM (20 mL), TEA (2.11G, 20.87 mmol) was added under ice-bath, stirred for 10min, and (Boc) ₂ O (2.19G, 10.02 mmol) was added and allowed to spontaneously rise to 25℃for 16hr. After the reaction, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (mobile phase DCM) to give Compound Int G-2 (2.4G).

Second step Synthesis of (S) -N-methyl- (6- (trifluoromethyl) -2, 3-dihydro-Benfurofuran-3-yl) carbamic acid tert-butyl ester (Compound Int G-3)

Compound Int G-2 (2.4G, 7.9 mmol) was dissolved in anhydrous THF (20 mL), naH (526.25 mg,13.16 mmol) was added in portions at 0deg.C and stirred for 0.5hr, and methyl iodide (1.37G, 9.65 mmol) was added dropwise thereto and the reaction was carried out overnight. After the reaction was completed, a small amount of methanol was added to quench the reaction, the reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=98:2) to give compound Int G-3 (2.7G).

Third step of Synthesis of (S) -N-methyl-6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-amine hydrochloride (Compound Int G)

Compound Int G-3 (2.7G, 8.51 mmol) was dissolved in DCM (15 mL), and a 4M solution of 1, 4-dioxane hydrochloride (5 mL) was added dropwise at 0deg.C and reacted at room temperature for 16hr. After the completion of the reaction, the reaction mixture was dried by spin-drying to give Compound Int G (2.07G).

MS(ESI,m/z):218.0[M+H]⁺。

EXAMPLE 1N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (5, 6,7, 8-tetrahydroquinoxalin-5-yl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step Synthesis of 5,6,7, 8-tetrahydroquinoxaline-1-oxide (Compound 1-2)

1-1 (10 G,74.53 mmol) was added to a 250mL flask and dissolved in DCM, m-CPBA (24.11 g,111.79 mmol) was added in portions under ice bath and after the addition was completed the reaction was allowed to warm naturally to 25℃for 16hr. After the reaction was completed, saturated sodium thiosulfate solution was added in ice bath to quench the peroxyacid, then saturated sodium bicarbonate aqueous solution was added and stirred until weak alkalinity was achieved and no bubbles were generated, then solid sodium chloride was added and extracted with DCM, and concentrated to give crude 1-2 (8.40 g), which was used directly in the next step without purification. MS (ESI, m/z): 151.1[ M+H ] ⁺.

Second step Synthesis of 5,6,7, 8-tetrahydroquinoxaline-5-acetate (Compound 1-3)

1-2 (4 G,26.64 mmol) was dissolved in glacial acetic acid (30 mL) and reacted at 140℃for 36hr. After the reaction, most of acetic acid is removed by rotary evaporation under reduced pressure to obtain a crude product, and the crude product is purified by silica gel column chromatography (mobile phase PE: EA=1:1) to obtain compounds 1-3 (4.04 g). MS (ESI, m/z): 193.1[ M+H ] ⁺.

Third step Synthesis of 5,6,7, 8-tetrahydroquinoxalin-5-ol (Compounds 1-4)

1-3 (4.04 G,21.00 mmol) was dissolved in THF (30 mL), and an aqueous solution (8 mL) of lithium hydroxide (2.20 g,52.51 mmol) was added dropwise thereto and reacted at room temperature for 6hr. After completion of the reaction, water was added and extracted with DCM, and concentrated to give Compound 1-4 (2.97 g), which was used directly after drying. MS (ESI, m/z): 151.1[ M+H ] ⁺.

Fourth step, synthesis of 7, 8-dihydroquinoxalin-5 (6H) -one (Compound 1-5)

1-4 (2.97 G,19.76 mmol) was dissolved in DCM (60 mL), and Dess-Martin oxidant was added thereto slowly in portions under ice-bath, and allowed to react naturally at room temperature for 5hr. After the reaction, most of the oxidant is removed by filtration, the filtrate is crude, and the crude is purified by silica gel column chromatography (mobile phase EA) to obtain the compounds 1-5 (1.23 g). MS (ESI, m/z): 149.1[ M+H ] ⁺.

Fifth step Synthesis of N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) -5,6,7, 8-tetrahydroquinoxalin-5-amine (Compounds 1-6)

Int D (356.65 mg,2.02 mmol) and 1-5 (300 mg,2.02 mmol) were added to DCE (10 mL), glacial acetic acid (243.18 mg,4.05 mmol) was added dropwise, and after stirring for 10min, sodium triacetoxyborohydride (643.71 mg,3.04 mmol) was added thereto and reacted at room temperature for 4hr. After the reaction was completed, the reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=95:5) to give compounds 1 to 6 (147 mg). MS (ESI, m/z): 309.1[ M+H ] ⁺.

Sixth step Synthesis of tert-butyl (3-methyl-5- (2-oxo-2- (((5, 6,7, 8-tetrahydroquinoxalin-5-yl) ((5- (trifluoromethyl) pyridin-2-yl) methyl) amino) acetamido) pyridin-2-yl) carbamate (Compound 1-7)

1-6 (40.13 Mg, 130.16. Mu. Mol), int A (42.28 mg, 143.18. Mu. Mol), pyBrop (72.81 mg, 156.19. Mu. Mol) were added to anhydrous DMF (3 mL), and DIPEA (25.23 mg, 195.24. Mu. Mol) was added dropwise thereto and reacted at 25℃for 1hr. After the reaction, water was added, extraction with ethyl acetate, drying, concentration to obtain crude product, purification by reverse phase HPLC to obtain compound 1-7 (15 mg). MS (ESI, m/z): 586.3[ M+H ] ⁺.

Seventh step Synthesis of N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (5, 6,7, 8-tetrahydroquinoxalin-5-yl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 1)

1-7 (15 Mg, 25.62. Mu. Mol) was added to a 4N hydrochloric acid-dioxane solution (1 mL) in ice bath, followed by reaction at room temperature at 25℃for 4hr. After the reaction, the temperature was reduced to 0 ℃ again, methanol was added for dilution, triethylamine was added dropwise for adjustment to be weakly alkaline, the mixture was concentrated under reduced pressure, and the crude product was purified by reversed phase HPLC to give compound 1 (4.69 mg). MS (ESI, m/z): 486.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.59–10.30(m,1H),8.89–8.82(m,1H),8.48–8.38(m,2H),8.23–8.16(m,1H),8.09–7.59(m,2H),7.55–7.33(m,1H),5.75–5.26(m,3H),5.15–4.07(m,2H),3.05–2.78(m,2H),2.14–1.77(m,7H).

Example 2 (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step (R) - (3-methyl-5- (2-oxo-2- ((1-pyrimidin-2-yl) ethyl)) ((5- (trifluoromethyl) pyridin-2-yl) methyl) amino) acetamido) pyridin-2-yl) carbamic acid tert-butyl ester (Compound 2-1) Synthesis

Int C (43 mg, 152.39. Mu. Mol), int A (45 mg, 152.39. Mu. Mol) were dissolved in anhydrous DMF (2 mL), DIPEA (29.54 mg, 228.59. Mu. Mol) was added, HATU (69.53 mg, 182.87. Mu. Mol) was added, and the reaction system was reacted at 25℃for 1hr. After the reaction was completed, water was added for dilution, extraction with ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, and separation and purification of crude Prep-HPLC to give Compound 2-1 (10 mg). MS (ESI, m/z): 560.1[ M+H ] ⁺.

Second step (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 2)

2-1 (10 Mg, 17.87. Mu. Mol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL), the reaction system was reacted at 25℃for 1hr, after the completion of the reaction, concentrated under reduced pressure, then dissolved in a proper amount of methanol, added with a few drops of TEA to adjust the pH to 7-8, concentrated under reduced pressure, and the crude product was isolated and purified by Prep-HPLC to give Compound 2 (3 mg). MS (ESI, m/z): 460.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.57–10.32(m,1H),8.92–8.66(m,3H),8.18–8.07(m,1H),8.07–7.87(m,1H),7.71–7.30(m,3H),5.76–5.56(m,2H),5.21–4.54(m,3H),2.09–1.88(m,3H),1.68–1.49(m,3H).

EXAMPLE 3 (R) -N ¹ - (5-carbamoyl-6-methoxypyridin-3-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - (5- (trifluoromethyl) pyridin-2-yl) methyl) -oxamide

First step, synthesis of 2-methoxy-5-nitronicotinamide (Compound 3-2)

3-1 (250 Mg,1.26 mmol), NH ₄ Cl (6755 mg,12.62 mmol), EDCI (803 mg,1.89 mmol) and HOBT (256 mg,1.89 mmol) were placed in a reaction flask, DMF (5 mL) was added, N-methylmorpholine (191 mg,1.89 mmol) was added, and then reacted at room temperature for 2hr. After the reaction was completed, 10mL of water was added to the reaction solution to quench the reaction, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE: ea=90:10) to give compound 3-2 (200 mg). MS (ESI, m/z): 198.1[ M+H ] ⁺.

Second step, synthesis of 5-Anyl-2-methoxy nicotinamide (Compound 3-3)

3-2 (250 Mg,1.27 mmol) was dissolved in MeOH (8 mL), pd/C (154 mg,0.13 mmol) was added, and after hydrogen was replaced, the reaction was maintained under a hydrogen atmosphere and allowed to react at room temperature for 16hr. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give Compound 3-3 (190 mg), MS (ESI, m/z): 168.1[ M+H ] ⁺.

Third step Synthesis of 2- ((5-carbamoyl-6-methoxypyridin-3-yl) -2- (oxoacetic acid ethyl ester) (Compound 3- -4)

3-3 (150 Mg,0.90 mmol) and DIPEA (174 mg,1.35 mmol) were dissolved in THF (5 mL) and oxalyl chloride monoethyl ester (123 mg,0.90 mmol) was slowly added and stirred at 25℃for 0.5hr after addition. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (10 ml×3), the organic phases were combined, the organic phases were successively washed with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 3-4 (130 mg). MS (ESI, m/z): 268.1[ M+H ] ⁺.

Fourth step Synthesis of 2- ((5-carbamoyl-6-methoxypyridin-3-yl) amino) -2-oxoethyl ester (Compound 3-5)

3-4 (250 Mg,0.94 mmol) and LiOH. H ₂ O (59 mg,1.40 mmol) were added to THF (1 mL) and H ₂ O (1 mL) and stirred at 25℃for 1hr. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to remove the solvent, purified by HPLC (H ₂ O [0.05% TFA ]: CAN=70:30), and lyophilized to give compound 3-5 (40 mg). MS (ESI, m/z): 240.1[ M+H ] ⁺.

Fifth step (R) -N ¹ - (5-carbamoyl-6-methoxypyridin-3-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - (5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 3)

3-5 (15 Mg, 62.71. Mu. Mol), int C (18 mg, 62.71. Mu. Mol), HATU (29 mg, 75.26. Mu. Mol) and DMF (2 mL) were added to the flask, dissolved with stirring, and then DIPEA (12 mg, 94.07. Mu. Mol) was added thereto, and the mixture was reacted at 25℃for 1hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by pre-HPLC and lyophilized to give compound 3 (10 mg). MS (ESI, m/z): 504.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.08–10.90(m,1H),8.85–8.72(m,3H),8.58–8.51(m,1H),8.45–8.39(m,1H),8.17–8.07(m,1H),7.81–7.66(m,2H),7.52–7.35(m,2H),5.77–5.69(m,1H),5.23–4.98(m,1H),4.94–4.59(m,1H),3.99–3.90(m,3H),1.69–1.51(m,3H).

EXAMPLE 4N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (bicyclo [1.1.1] pent-1-yl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step Synthesis of N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) bicyclo [1.1.1] pent-1-amine (Compound 4-2)

4-1 (177.57 Mg,1.48 mmol) and Int C-1 (200 mg,1.14 mmol) were dissolved in anhydrous DCM (5 mL) and AcOH (137.17 mg,2.28 mmol) was added and the resulting mixture stirred at 25℃for 30min. NaBH (OAc) ₃ (363.10 mg,1.71 mmol) was then added and the reaction was continued at 25℃for 1.5hr. After completion of the reaction, the reaction was quenched with methanol, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase PE: ea=60:40) to give compound 4-2 (40 mg). MS (ESI, m/z): 243.1[ M+H ] ⁺.

Second step Synthesis of tert-butyl (5- (2- (bicyclo [1.1.1] pent-1-yl ((5- (trifluoromethyl) pyridin-2-yl) methyl) amino) -2-oxoacetamide) -3-methylpyridin-2-yl) carbamate (Compound 4-3)

4-2 (35 Mg, 144.48. Mu. Mol), int A (42.67 mg, 144.48. Mu. Mol) were added to the flask and dissolved in DMF (2 mL), DIPEA (28.01 mg, 216.73. Mu. Mol), HATU (65.92 mg, 173.38. Mu. Mol) were added, and after the completion of the addition, the reaction system was reacted at 25℃for 1hr, after the completion of the reaction, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was isolated and purified by Prep-TLC (PE: EA=1:1) to give compound 4-3 (30 mg). MS (ESI, m/z): 520.2[ M+H ] ⁺.

Third step Synthesis of N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (bicyclo [1.1.1] pent-1-yl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 4)

4-4 (30 Mg, 57.75. Mu. Mol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL), the reaction system was reacted at 25℃for 1hr, after the completion of the reaction, concentrated under reduced pressure, then added with an appropriate amount of methanol, pH was adjusted to 7-8 by adding a few drops of TEA, concentrated under reduced pressure, and the crude product was isolated and purified by Prep-HPLC to give Compound 4 (12 mg). MS (ESI, m/z): 420.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ11.22–11.00(m,1H),8.99–8.87(m,1H),8.36–8.18(m,2H),7.88–7.79(m,2H),7.65–7.50(m,1H),4.99–4.72(m,2H),2.48–2.36(m,1H),2.24–2.13(m,3H),2.08–1.95(m,6H).

The following compounds were prepared by the methods and general procedures described in example 4, and the desired additional starting materials were obtained commercially or synthesized by those skilled in the art of organic synthesis using conventional reactions from commercially available reagents.

Example 5 (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (1- (6-fluoropyridin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl)) methyl) oxamide

First step Synthesis of 6-fluoro-N-methoxy-N-methylpyridine amide (Compound 5-3)

5-1 (3 G,21.26 mmol), 5-2 (2.28 g,23.39 mmol) and HATU (9.70 g,25.50 mmol) were placed in a reaction flask, DMF (50 mL) was added, DIPEA (8.24 g,63.78 mmol) was slowly added under water bath cooling, and then reacted at room temperature. After the reaction was completed, 100mL of water was added to the reaction solution to quench the reaction, ethyl acetate (60 ml×3) was extracted, the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE: ea=90:10-80:20) to give compound 5-3 (3 g). MS (ESI, m/z): 185.1[ M+H ] ⁺.

Second step Synthesis of 1- (6-fluoropyridin-2-yl) ethan-1-one (Compound 5-4)

5-3 (1.5 G,8.14 mmol) was dissolved in dry THF (20 mL), cooled to 0deg.C, then methyl magnesium bromide (0.5M, 17.92 mL) was slowly added, and the reaction was continued at 0deg.C. After the reaction is finished, adding saturated ammonium chloride solution into the reaction solution to quench the reaction, adding 60mL of water to dilute the reaction solution, extracting with ethyl acetate (50 mL x 3), merging organic phases, washing the organic phases with clear water and saturated saline water sequentially, drying with anhydrous sodium sulfate, filtering the solution, and concentrating the filtrate under reduced pressure until the solution is dried to obtain a crude product. The crude product was purified by silica gel column chromatography (EA: pe=10:90) to give compound 5-4 (700 mg).

Third step (R) -N- (1- (6-fluoropyridin-2-yl) -ethylene) -2-methylpropan-2-sulfinamide (Compound 5-5)

Into the reaction flask were charged 5-4 (700 mg,5.03 mmol), int B-2 (1.09 g,9.00 mmol), ti (iPrO) ₄ (2.86 g,10.06mmol,2.98 mL) and THF (30 mL), nitrogen-blanketed, and reacted at 70℃for 48hr. After the reaction is finished, cooling to room temperature, and directly using the mixture for the next reaction. MS (ESI, m/z): 243.1[ M+H ] ⁺.

Fourth step (R) -N- ((R) - (1- (6-fluoropyridin-2-yl) ethyl) -2-methylpropan-2-sulfinamide (Compound 5-6)

To the flask was added 5-5 (1.2 g,4.95 mmol), THF (30 mL), naBH ₄ (374 mg,9.90 mmol), nitrogen blanket, and reacted at 25℃for 1hr. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (50 ml×3), the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (EA: pe=35:65) to give compound 5-6 (710 mg). MS (ESI, m/z): 245.1[ M+H ] ⁺.

Fifth step (R) -1- (6-fluoropyridin-2-yl) ethane-1-amine (Compound 5-7) Synthesis

5-6 (700 Mg,2.86 mmol), meOH (10 mL), 4N HCl-dioxane (2.86 mL), nitrogen blanket, 25℃were added to the flask and reacted for 2hr. After the reaction was completed, most of the solvent was removed by concentration under reduced pressure, then diluted with saturated NaHCO ₃ solution, extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 5-7 (370 mg). MS (ESI, m/z): 141.1[ M+H ] ⁺.

Sixth step (R) -1- (6-fluoropyridin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (Compound 5-8) Synthesis

5-8 (370 Mg,2.64 mmol), int C-1 (370 mg,2.11 mmol), DCE (20 mL), acetic acid (238 mg,3.96 mmol) were added to the flask and reacted at 25℃for 5hr under nitrogen. Sodium triacetoxyborohydride (840 mg,3.96 mmol) was added thereto and reacted at 25℃for 2hr. After the reaction was completed, the reaction mixture was quenched with water, extracted with DCM (50 ml×3), the organic phases were combined, washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (EA: pe=35:65) to give compound 5-8 (85 mg). MS (ESI, m/z): 300.1[ M+H ] ⁺.

Seventh step Synthesis of tert-butyl (R) - (5- (2- ((1- (6-fluoropyridin-2-yl) ethyl) ((5- (trifluoromethyl) pyridin-2-yl) methyl) amino) -2-oxoacetamide) -3-methylpyridin-2-yl) carbamate (Compound 5-9)

5-8 (15 Mg, 50.12. Mu. Mol), int A (22 mg, 75.18. Mu. Mol), HATU (23 mg, 60.15. Mu. Mol) and DMF (2 mL) were added to the flask, dissolved with stirring, and then DIPEA (10 mg, 75.18. Mu. Mol) was added thereto, and the mixture was reacted at 25℃for 1hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (50 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep. plate, developer (DCM: meoh=10:1) to give compounds 5-9 (10 mg). MS (ESI, m/z): 477.1[ M+H-Boc ] ⁺.

Eighth step (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - (1- (6-fluoropyridin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl)) methyl) oxamide (Compound 5)

5-9 (10 Mg, 17.34. Mu. Mol) in 4N hydrochloric acid-dioxane solution (1 mL), nitrogen blanket, 25℃were added to the flask and reacted for 2hr. The reaction solution is concentrated under reduced pressure to obtain a crude product, and TEA is added to adjust the pH to be alkaline to obtain the crude product. The crude product was purified by Pre-HPLC to give compound 5 (4 mg). MS (ESI, m/z): 477.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.66–10.35(m,1H),8.82–8.75(m,1H),8.12–7.87(m,3H),7.57–7.52(m,1H),7.43–7.31(m,2H),7.07–6.99(m,1H),5.75–5.53(m,3H),5.11–4.91(m,1H),4.79–4.57(m,1H),2.06–1.95(m,3H),1.61–1.46(m,3H).

EXAMPLE 16 (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - ((2-oxo-1, 2,3, 4-tetrahydroquinolin-6-yl) methyl) -N ² - (1- (pyrimidin-2-yl) ethyl) oxamide

First step Synthesis of 6-vinyl-3, 4-dihydroquinolin-2 (1H) -one (Compound 16-2)

16-1 (2.0 G,8.85 mmol) was added to a 50mL flask, followed by ethylene potassium trifluoroborate (1.42 g,10.62 mmol), pd (PPh ₃)₂Cl₂ (620 mg, 884.68. Mu. Mol) and Na ₂CO₃ (1.88 g,17.69 mmol), 1, 4-dioxane (10 mL) and H ₂ O (1 mL) were added to dissolve, and after nitrogen protection, the reaction was allowed to proceed to 100℃for 8hr, water was added and ethyl acetate was used to extract after completion, and the crude product was concentrated and purified by silica gel column chromatography (mobile phase PE: EA=1:1) to give compound 16-2 (1.22 g). MS (ESI, m/z): 174.1[ M+H ] ⁺.

Second step Synthesis of 2-oxo-1, 2,3, 4-tetrahydroquinoline-6-carbaldehyde (Compound 16-3)

16-2 (500 Mg,2.89 mmol) was dissolved in a mixed solvent of 1, 4-dioxane (5 mL) and water (1 mL), and potassium osmium dihydrate (1599 mg, 433.00. Mu. Mol) and NaIO ₄ (2.49 g,11.55 mmol) were added and reacted at 25℃for 4hr. After the reaction, water was added and extracted with ethyl acetate, and the crude product was concentrated, and purified by silica gel column chromatography (mobile phase DCM: meoh=97:3) to give compound 16-3 (142 mg). MS (ESI, m/z): 175.1[ M+H ] ⁺.

Third step (R) -6- (((1- (pyrimidin-2-yl) ethyl) amino) methyl) -3, 4-dihydroquinolin-2 (1H) -one (compound 16-4) synthesis

16-3 (35 Mg, 121.80. Mu. Mol), int B (50 mg, 121.80. Mu. Mol) were dissolved in DCM (5 mL), acetic acid (14 mg, 243.59. Mu. Mol) was added dropwise thereto, and after stirring at room temperature for 10min, sodium triacetoxyborohydride (39 mg, 182.70. Mu. Mol) was added and reacted at room temperature for 5hr. After the reaction was completed, methanol was added for dissolution and then concentrated, and the crude product was purified by silica gel column chromatography (mobile phase DCM: meoh=90:10) to give compound 16-4 (25 mg). MS (ESI, m/z): 283.2[ M+H ] ⁺.

Fourth step Synthesis of tert-butyl (R) - (3-methyl-5- (2-oxo-2- (((2-oxo-1, 2,3, 4-tetrahydroquinolin-6-yl) methyl) (1- (pyrimidin-2-yl) ethyl) amino) acetamido) pyridin-2-yl) carbamate (Compound 16-5)

16-4 (25 Mg, 88.55. Mu. Mol), int A (31 mg, 106.26. Mu. Mol), HATU (84 mg, 221.36. Mu. Mol), DIPEA (45 mg, 354.17. Mu. Mol) were added to anhydrous DMF (3 mL) and reacted at 25℃for 1hr. After the reaction, water was added, extraction with ethyl acetate, drying, concentration to obtain crude product, purification by reverse phase HPLC to obtain intermediate 16-5 (5 mg). MS (ESI, m/z): 560.2[ M+H ] ⁺.

Fifth step (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - ((2-oxo-1, 2,3, 4-tetrahydroquinolin-6-yl) methyl) -N ² - (1- (pyrimidin-2-yl) ethyl) oxamide (compound 16) Synthesis

16-5 (5 Mg, 8.93. Mu. Mol) was dissolved in DCM (5 mL) in ice bath, and 4N hydrochloric acid-1, 4-dioxane solution (0.5 mL) was added dropwise and reacted at 25℃for 1hr. After the reaction, the temperature was reduced to 0℃again, methanol was added for dilution, triethylamine was added dropwise for adjustment to weakly alkaline, and the crude product was concentrated under reduced pressure and purified by reversed phase HPLC to give 16 (2.51 mg). MS (ESI, m/z): 460.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.53–10.28(m,1H),10.06–9.88(m,1H),8.80–8.70(m,2H),8.07–7.86(m,1H),7.54–7.31(m,2H),7.05–6.88(m,2H),6.74–6.65(m,1H),5.68–5.43(m,3H),4.70–4.23(m,2H),2.81–2.72(m,2H),2.44–2.36(m,2H),2.06–1.96(m,3H),1.63–1.51(m,3H).

EXAMPLE 19 (R) -N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step Synthesis of (R) -N ¹ - (7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² - (1- (pyrimidin-2-) yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 19-1)

Int C(29.30mg,103.80μmol)、Int E(40.00mg,103.80μmol)、HATU(47.36mg,124.55μmol)、DIPEA(20.12mg,155.69μmol) Was added to anhydrous DMF (3 mL) and reacted at 25℃for 5hr. After the reaction, water was added, extraction with ethyl acetate, drying, concentration to obtain crude product, purification by reverse phase HPLC to obtain intermediate 19-1 (8 mg). MS (ESI, m/z): 650.2[ M+H ] ⁺.

Second step (R) -N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 19)

19-1 (8 Mg, 8.93. Mu. Mol) was dissolved in DCM (5 mL) in ice bath, and hydrochloric acid-dioxane solution (0.5 mL) was added dropwise and reacted at room temperature of 25℃for 1hr. After the reaction, the temperature was reduced to 0℃again, triethylamine was added dropwise thereto to adjust the reaction mixture to weakly basic, the mixture was concentrated under reduced pressure, and the crude product was purified by reversed phase HPLC to give 19 (1.83 mg). MS (ESI, m/z): 500.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.76–10.54(m,1H),8.86–8.78(m,1H),8.78–8.74(m,1H),8.17–8.07(m,1H),7.89–7.46(m,4H),7.42–7.35(m,1H),6.31–6.17(m,2H),5.83–5.64(m,1H),4.96–4.67(m,2H),4.32–4.18(m,3H),1.69–1.52(m,3H).

The following compounds were prepared by the methods and general procedures described in example 19, and the desired additional starting materials were obtained commercially or synthesized by those skilled in the art of organic synthesis using conventional reactions from commercially available reagents.

EXAMPLE 20 (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - ((5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methyl) -N ² - (1- (pyrimidin-2-yl) ethyl) oxamide

First step Synthesis of 5- (1-methyl-1H-pyrazol-4-yl) pyridine carboxaldehyde (Compound 20-3)

20-1(500mg,2.69mmol)、20-2(587mg,2.82mmol)、Pd(dppf)Cl₂(195mg,269μmol)、K₂CO₃(557mg,4.03mmol) And 1, 4-dioxane (15 mL) and water (1 mL) were added to the flask, and the mixture was reacted at 80℃for 16hr under nitrogen. After the reaction was completed, water was added to the reaction solution to dilute, extraction was performed with ethyl acetate (50 ml×3), the organic phases were combined, the organic phases were washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (DCM: meoh=96:4) to give compound 20-3 (320 mg). MS (ESI, m/z): 188.1[ M+H ] ⁺.

Second step (R) -N- ((5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethan-1-amine (Compound 20-4) Synthesis

Into the reaction flask were added 20-3 (50 mg, 267.10. Mu. Mol), int B (33 mg, 267.10. Mu. Mol), DCM (3 mL), acetic acid (32 mg, 534.19. Mu. Mol), and the mixture was reacted at 25℃for 5hr under nitrogen. Sodium triacetoxyborohydride (85 mg, 400.65. Mu. Mol) was added thereto and reacted at 25℃for 5hr. After the reaction was completed, the reaction mixture was quenched with water, extracted with DCM (30 ml×3), the organic phases were combined, washed successively with clear water, saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (DCM: meoh=95:5) to give compound 20-4 (70 mg). MS (ESI, m/z): 295.1[ M+H ] ⁺.

Third step Synthesis of tert-butyl (R) - (3-methyl-5- (2- (((5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methyl) (1- (pyrimidin-2-yl) ethyl) amino) -2-oxoacetamido) pyridin-2-yl) carbamate (Compound 20-5)

To the flask were added 20-4 (25 mg, 84.66. Mu. Mol), int A (25 mg, 84.66. Mu. Mol), HATU (39 mg, 101.59. Mu. Mol) and DMF (2 mL), and after stirring to dissolve, DIPEA (33 mg, 253.99. Mu. Mol) was added, and the mixture was reacted at 25℃for 2hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (50 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep. plate (DCM: meoh=10:1) to give compound 20-5 (20 mg). MS (ESI, m/z): 572.2[ M+H ] ⁺.

Fourth step (R) -N ¹ - (6-amino-5-methylpyridin-3-yl) -N ² - ((5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl) methyl) -N ² - (1- (pyrimidin-2-yl) ethyl) oxamide (Compound 20) Synthesis

Into the flask was charged 20-5 (20 mg, 34.99. Mu. Mol) and 4M HCl-1, 4-dioxane (2 mL), nitrogen-blanketed, and reacted at 25℃for 2hr. The reaction solution is concentrated under reduced pressure to obtain a crude product, and TEA is added to adjust the pH to be alkaline to obtain the crude product. The crude product was purified by Pre-HPLC to give compound 20 (5 mg). MS (ESI, m/z): 472.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.55–10.37(m,1H),8.78–8.74(m,2H),8.68–8.64(m,1H),8.21(s,1H),8.07–7.90(m,2H),7.87–7.82(m,1H),7.54–7.17(m,3H),5.69–5.56(m,3H),5.08–4.83(m,1H),4.82–4.38(m,1H),3.88–3.86(m,3H),2.04–1.94(m,3H),1.64–1.48(m,3H).

EXAMPLE 22N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -isobutyl-N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step Synthesis of 2-methyl-N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) propan-1-amine (Compound 22-2)

Int C-1 (383.08 mg,2.19 mmol) and 22-1 (200.00 mg,2.73 mmol) were added to anhydrous DCM (10 mL), acOH (328.43 mg,5.47 mmol) was added dropwise and stirred for 10min, sodium triacetoxyborohydride (869.36 mg,5.47 mmol) was added and reacted at 25℃for 1hr. After the reaction, water was added, extraction with ethyl acetate, drying, concentration gave a crude product, which was purified by column chromatography on silica gel (mobile phase DCM: meoh=95:5) to give compound 22-2 (510 mg). MS (ESI, m/z): 233.2[ M+H ] ⁺.

Second step Synthesis of N ¹ - (7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -isobutyl-N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 22-3)

Int E (40.00 mg, 62.28. Mu. Mol), DIPEA (16.10 mg, 124.55. Mu. Mol) were added to anhydrous DMF (5 mL), HATU (35.52 mg, 124.55. Mu. Mol) was added at 0℃and after stirring for 5min 22-2 (14.46 mg, 62.28. Mu. Mol) was added and the reaction was carried out at 25℃for 1hr. After the reaction, water was added and stirred, ethyl acetate was extracted and concentrated to give a crude product, which was purified by column chromatography on silica gel (mobile phase DCM: meoh=95:5) to give compound 22-3 (19.20 mg). MS (ESI, m/z): 600.2[ M+H ] ⁺.

Third step Synthesis of N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -isobutyl-N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 22)

22-3 (19.20 Mg, 32.02. Mu. Mol) was dissolved in DCM (5 mL) under ice and TFA (2 mL) was added dropwise and reacted at 25℃for 2hr. After the reaction, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution, extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by reverse phase HPLC to obtain Compound 22 (2.49 mg). MS (ESI, m/z): 450.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.74–10.56(m,1H),8.96–8.91(m,1H),8.32–8.15(m,1H),7.89–7.79(m,1H),7.70–7.55(m,2H),6.27–6.22(m,1H),4.95–4.79(m,2H),4.28–4.24(m,3H),3.26–3.25(m,2H),2.07–1.95(m,2H),0.91–0.84(m,6H).

EXAMPLE 23 (R) -N ¹ - (4-amino-1-methyl-1H-pyrazolo [4,3-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step Synthesis of (R) -N ¹ - (4- ((4-methoxybenzyl) amino) -1-methyl-1H-pyrazolo [4,3-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 23-1)

Int C (30 mg, 106.28. Mu. Mol) and HATU (12.84 mg, 33.77. Mu. Mol) were dissolved in anhydrous DMF (2 mL), and the resulting mixture was stirred at 25℃for 30min, then Int F (37.77 mg, 106.28. Mu. Mol) was added thereto, and the reaction system was allowed to react at 25℃for 1hr. After the reaction was completed, water was added for dilution, ethyl acetate extraction, saturated brine, dried over anhydrous sodium sulfate, and filtered, and the crude product was isolated and purified by Prep-TLC (DCM: meoh=10:1) to give compound 23-1 (8 mg). MS (ESI, m/z): 620.2[ M+H ] ⁺.

Second step (R) -N ¹ - (4-amino-1-methyl-1H-pyrazolo [4,3-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 23)

23-1 (8 Mg, 8.93. Mu. Mol) was dissolved in TFA (2 mL) in ice bath and heated to 90℃for 1hr. After the reaction, the mixture was concentrated by distillation under reduced pressure, then dissolved in methanol, and triethylamine was added dropwise thereto to adjust the mixture to weakly alkaline, the mixture was concentrated under reduced pressure, and the crude product was purified by reverse phase pre-HPLC to give Compound 23 (1.83 mg). MS (ESI, m/z): 500.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.51–9.92(m,1H),8.88–8.65(m,3H),8.23–8.06(m,2H),7.67–7.47(m,1H),7.44–7.37(m,1H),7.15–6.76(m,2H),5.82–5.76(m,1H),5.43–5.21(m,1H),5.05–4.90(m,1H),4.78–4.53(m,1H),4.08–3.89(m,3H),1.67–1.53(m,3H).

EXAMPLE 28 (R) -N ¹ - (4-amino-1, 3-dihydrofuro [3,4-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide

First step, synthesis of methyl pyridine 3, 4-dicarboxylate (Compound 28-2)

28-1 (30 G,179.51 mmol) and SOCl ₂ (100 mL) were added to a reaction flask, reacted at 80℃for 3 hours, the reaction solution was dried by spin, SOCl ₂ (100 mL) was added again, the reaction solution was dried by spin, and added dropwise to MeOH (200 mL), after stirring at room temperature for 0.5 hours, the reaction solution was distilled off under reduced pressure to remove the solvent, ethyl acetate was dissolved, an aqueous sodium hydrogencarbonate solution was washed twice, and the organic phase was dried over sodium sulfate and distilled off under reduced pressure to remove the solvent to give compound 28-2 (30 g), MS (ESI, m/z): 196.1[ M+H ] ⁺.

Second step Synthesis of 3, 4-bis (methoxycarbonyl) pyridine 1-oxide (Compound 28-3)

28-2 (30 G,153.71 mmol) was dissolved in DCM (300 mL), m-CPBA (49.73 g,230.57 mmol) was added in portions, stirred overnight at room temperature, TLC monitored no starting material remained, slowly aqueous sodium thiosulfate solution (150 mL) was added, stirred for 1 hour, extracted three times with dichloromethane, the organic phases combined, dried over sodium sulfate and the solvent removed by distillation under reduced pressure, column chromatography (5% EA-100% EA) gave compound 28-3 (26 g), MS (ESI, m/z): 212.1[ M+H ] ⁺.

Third step, synthesis of methyl 2-chloropyridine 3, 4-dicarboxylate (Compound 28-4)

28-3 (26.00 G,123.12 mmol) was added to POCl ₃ (150 mL), reacted overnight at 100℃and monitored by LCMS to complete the reaction, the reaction solution was cooled, the solvent was distilled off under reduced pressure, poured into ice water, the sodium bicarbonate condition pH was about 6, extracted with ethyl acetate, the organic phases were combined, the organic phases were dried over sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography (5% EA-7% EA) gave compound 28-4 (12 g), MS (ESI, m/z): 230.1[ M+H ] ⁺.

Fourth step (Synthesis of 2-chloropyridine-3, 4-diyl) dimethanol (Compound 28-5)

28-4 (12 G,52.26 mmol) was dissolved in EtOH (120 mL), naBH ₄ (11.86 g,313.57 mmol) was added in portions, and after the addition, the reaction was completed at room temperature for 2 hours, LCMS was monitored to adjust the pH to about 5, formic acid was added dropwise, the solvent was distilled off under reduced pressure, and column chromatography (50% EA-100% EA) was performed to give compound 28-5 (7.87 g), MS (ESI, m/z): 174.1[ M+H ] ⁺.

Fifth step, synthesis of 4-chloro-1, 3-dihydrofuro [3,4-c ] pyridine (Compound 28-6)

28-5 (7.87 G,45.33 mmol) was dissolved in DCM (180 mL), mnO ₂ (7.88 g,90.67 mmol) was added in portions, et ₃ SiH (32 mL) and TFA (64 mL) were added dropwise in sequence, the reaction was allowed to proceed overnight at room temperature, LCMS was monitored for completion, the solvent was removed by distillation under reduced pressure, and column chromatography (5% EA-20% EA) gave 28-6 (2.69 g), MS (ESI, m/z): 156.1[ M+H ] ⁺.

Sixth step Synthesis of N- (2, 4-dimethoxybenzyl) -1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 28-7)

28-6 (1 G,6.43 mmol), int E-3 (2.15 g,12.86 mmol), t-BuNa (2.47 g,25.71 mmol), BINAP (400.22 mg, 642.75. Mu. Mol) and Pd ₂(dba)₃ (294.29 mg, 321.38. Mu. Mol) were dissolved in toluene (30 mL), purged with nitrogen, and reacted overnight at 100 ℃. The solvent was distilled off under reduced pressure, and the resultant was subjected to column chromatography (10% -30% EA) to give 28-7 (1.6 g), MS (ESI, m/z): 287.1[ M+H ] ⁺.

Seventh step Synthesis of 1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 28-8)

28-7 (1.6 G,5.59 mmol) was dissolved in TFA (10 mL), reacted at room temperature for 1 hour, LCMS monitored the reaction was complete, the solvent was distilled off under reduced pressure, and Flash was purified to give compound 28-8 (470 mg), MS (ESI, m/z): 137.1[ M+H ] ⁺.

Eighth step, synthesis of 7-bromo-1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 28-9)

28-8 (460 Mg,3.38 mmol) was dissolved in MeCN (2 mL), NBS (661.46 mg,3.72 mmol) was added in portions and reacted at room temperature for 2 hours, LCMS monitored no starting material remained, the solvent was distilled off under reduced pressure, and the compound 28-9 (700 mg) was obtained by column chromatography, MS (ESI, m/z): 215.0,217.0[ M+H ] ⁺.

Ninth step Synthesis of 7-bromo-N, N-bis (4-methoxybenzyl) -1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 28-10)

28-9 (700 Mg,3.26 mmol) was dissolved in DMF (10 mL), naH (520.82 mg,13.02 mmol) was added in portions at 0℃and then reacted at 0℃for 0.5 hours, followed by drop-wise addition PMBCl (1.53 g,9.77 mmol) and reaction at room temperature for 2 hours. Quenched with water, extracted with ethyl acetate, washed with dilute brine, the organic phase dried over sodium sulfate, the solvent removed by distillation under reduced pressure, and column chromatography (0% EA-20% EA) to give 28-10 (0.93 g), MS (ESI, m/z): 455.1,457.1[ M+H ] ⁺.

Tenth step Synthesis of 7- ((diphenylmethylene) amino) -N, N-bis (4-methoxybenzyl) -1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 28-11)

28-10(0.93g,2.04mmol),Int E-5(740.30mg,4.08mmol),t-BuONa(588.85mg,6.13mmol),BINAP(127.18mg,204.24μmol) And Pd ₂(dba)₃ (93.51 mg, 102.12. Mu. Mol) were dissolved in 1, 4-dioxane (12 mL) under nitrogen and reacted overnight at 80 ℃. The solvent was distilled off under reduced pressure, and the resultant mixture was subjected to column chromatography (0% EA-10% EA) to give 28-11 (800 mg), MS (ESI, m/z) 556.3[ M+H ] ⁺.

Eleventh step Synthesis of N ⁴,N⁴ -bis (4-methoxybenzyl) -1, 3-dihydrofuro [3,4-c ] pyridine-4, 7-diamine (Compound 28-12)

28-11 (0.93 G,1.67 mmol) was dissolved in DCM (12 mL), then 4N HCl-1, 4-dioxane (4 mL) was added and reacted at room temperature for 2 hours, LCMS monitored that the reaction was complete, the solvent was distilled off under reduced pressure and the next step was directly taken to give 28-12 (500 mg), MS (ESI, m/z): 392.2[ M+H ] ⁺.

Twelfth step Synthesis of Ethyl 2- ((4- (bis (4-methoxybenzyl) amino) -1, 3-dihydrofuro [3,4-c ] pyridin-7-yl) amino) -2-oxoacetate (Compound 28-13)

28-12 (500 Mg,1.28 mmol) was dissolved in THF (3 mL), DIEA (660.31 mg,5.11 mmol) was added, and oxalyl chloride monoethyl ester (261.58 mg,1.92 mmol) was added dropwise and reacted at room temperature for 1 hour. LCMS was monitored for completion, quenched by the addition of methanol, distilled off under reduced pressure and column chromatographed to give compound 28-13 (370 mg), MS (ESI, m/z): 492.2[ M+H ] ⁺.

Thirteenth step Synthesis of 2- ((4- (bis (4-methoxybenzyl) amino) -1, 3-dihydrofuro [3,4-c ] pyridin-7-yl) amino) -2-oxoacetic acid (Compound 28-14)

28-13 (370 Mg, 752.74. Mu. Mol) was dissolved in THF (5 mL), and a solution of LiOH H ₂ O (63.18 mg,1.51 mmol) in H ₂ O (1 mL) was added dropwise and reacted at room temperature for 2 hours. LCMS monitors completion of the reaction, and the reaction mixture was distilled off under reduced pressure to remove the solvent and lyophilized to give Compound 28-14 (330 mg), MS (ESI, m/z): 464.2[ M+H ] ⁺.

Synthesis of (R) -N ¹ - (4- (bis (4-methoxybenzyl) amino) -1, 3-dihydrofuro [3,4-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl)) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 28-15)

Int C (9.14 mg, 32.36. Mu. Mol) was dissolved in DMF (1 mL), HATU (24.61 mg, 64.73. Mu. Mol) was then added to the flask and stirred for 20 min, 28-14 (15 mg, 32.36. Mu. Mol) of DMF solution was added dropwise and the reaction was allowed to proceed overnight at room temperature. LCMS monitored no starting material remaining, ethyl acetate dilution, dilute brine washing of the organic phase, drying of the organic phase over sodium sulfate, distillation of the solvent under reduced pressure, and scraper (DCM: meoh=20:1) gave compound 28-15 (6 mg), MS (ESI, m/z): 728.3[ m+h ] ⁺.

Fifteenth step (R) -N ¹ - (4-amino-1, 3-dihydrofuro [3,4-c ] pyridin-7-yl) -N ² - (1- (pyrimidin-2-yl) ethyl) -N ² - ((5- (trifluoromethyl) pyridin-2-yl) methyl) oxamide (Compound 28)

28-15 (6 Mg, 8.24. Mu. Mol) was dissolved in TFA (2 mL) and reacted at 90℃for 4 hours. LCMS was monitored for no starting material remaining, the reaction was distilled off under reduced pressure to remove solvent, and aqueous ammonia was used to adjust the base to give Compound 28 (1.8 mg), MS (ESI, m/z): 488.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.48-10.36(m,1H),8.83-8.82(m,1H),8.78-8.74(m,2H),8.15-8.11(m,1H),7.80-7.61(m,1H),7.45-7.36(m,2H),6.01-5.95(m,2H),5.80-5.60(m,1H),5.24-4.90(m,2H),4.87-4.80(m,2H),4.76-4.56(m,2H),1.65-1.50(m,3H).

The following compounds were prepared by the methods and general procedures described in example 28, and the desired additional starting materials were obtained commercially or synthesized by those skilled in the art of organic synthesis using conventional reactions from commercially available reagents.

EXAMPLE 70 (S) -N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) oxamide

First step (S) Synthesis of N ¹ - (7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) oxamide (Compound 70-1)

To the reaction flask were added Int E (189.92 mg, 394.25. Mu. Mol), int G (100 mg, 394.25. Mu. Mol) dissolved in anhydrous DMF (10 mL), DIPEA (152.86 mg,1.18 mmol) and HATU (224.86 mg, 591.37. Mu. Mol) were added sequentially and the reaction was completed at 25℃for 1hr. After the completion of the reaction, water was added for dilution, extraction with ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, and separation and purification of the crude product by silica gel column chromatography (DCM: meoh=95:5) gave compound 70-1 (220 mg). MS (ESI, m/z): 585.2[ M+H ] ⁺.

Second step (S) Synthesis of N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) oxamide (Compound 70)

70-1 (220 Mg, 376.36) was dissolved in DCM (10 mL), TFA (2 mL) was added, the reaction system was reacted at 25℃for 2hr, after the completion of the reaction, concentrated under reduced pressure, EA was dissolved, saturated aqueous sodium bicarbonate was washed, saturated brine was washed, the organic layer was dried over anhydrous sodium sulfate, filtered, and the crude product was isolated and purified by Prep-HPLC to give compound 70 (130 mg). MS (ESI, m/z): 435.1[ M+H ] ⁺.

¹H NMR(400MHz,DMSO)δ10.69(s,1H),8.09-7.81(m,2H),7.74-7.53(m,1H),7.44-7.23(m,2H),6.37-5.83(m,3H),4.89-4.62(m,2H),4.29(s,3H),2.82-2.56(m,3H).

EXAMPLE 73 (S) -N ¹ - (8-Aminoimidazo [1,5-a ] pyrazin-5-yl) -N ² -methyl-N ² - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) oxamide

First step Synthesis of 5-bromo-1- (4-methoxybenzyl) pyrazin-2 (1H) -one (Compound 73-3)

DMF (35 mL) and NaH (1.31 g,32.86 mmol) were added to the flask, the temperature was lowered in an ice-water bath, then a solution of 73-1 (5 g,28.57 mmol) in THF (15 mL) was slowly added, the mixture was reacted at 0℃for 30min under nitrogen protection, 73-2 (4.92 g,31.43mmol,4.26 mL) was added, and the mixture was naturally warmed to room temperature and reacted overnight. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (60 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=98:2) to give compound 73-3 (6.74 g). MS (ESI, m/z): 295.3[ M+H ] ⁺.

Second step Synthesis of 5-bromo-7- (4-methoxybenzyl) imidazo [1,5-a ] pyrazin-8 (7H) -one (Compound 73-4)

NaH (945 mg,23.63 mmol) and THF (15 mL) were added to the flask, the temperature was reduced in an ice-water bath, and a solution of 73-3 (3.1 g,10.50 mmol) and TosMIC (2.26 g,11.55 mmol) in THF (15 mL) was added and the mixture was reacted at 0℃for 2hr under nitrogen. After the reaction was completed, water was added to dilute, EA (60 ml x 3) was used for extraction, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=60:40) to give compound 73-4 (2.75 g). MS (ESI, m/z): 334.0[ M+H ] ⁺.

Third step Synthesis of 5-bromoimidazo [1,5-a ] pyrazin-8 (7H) -one (Compound 73-5)

73-4 (450 Mg,1.35 mmol), anisole (2.62 g,24.24 mmol), trifluoromethanesulfonic acid (2.43 g,16.16mmol,1.43 mL), TFA (6 mL), nitrogen blanket, 40℃were added to the flask and reacted for 2hr. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, most of the solvent was removed by spinning, and then isopropyl ether was added to the mixture to pulp, followed by filtration, and the cake was washed with isopropyl ether and dried to give compound 73-5 (320 mg). MS (ESI, m/z): 213.9[ M+H ] ⁺.

Fourth step Synthesis of 5-bromo-8-chloroimidazo [1,5-a ] pyrazine (Compound 73-6)

73-5 (3 G,14.02 mmol), DIPEA (3.62 g,28.03 mmol), POCl ₃ (30 mL), nitrogen blanket, 100℃were added to the flask and reacted for 16hr. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, diluted with saturated NaHCO ₃ solution, extracted with EA (50 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 73-6 (3.2 g). MS (ESI, m/z): 231.8[ M+H ] ⁺.

Fifth step Synthesis of 5-bromo-N- (2, 4-dimethoxybenzyl) imidazo [1,5-a ] pyrazin-8-amine (Compound 73-7)

73-6 (3.2 G,13.77 mmol), etOH (100 mL), int E-3 (4.60 g,27.53 mmol), nitrogen blanket, 80℃were added to the flask and reacted for 16hr. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (50 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=98:2) to give compound 73-7 (4.4 g). MS (ESI, m/z): 363.1[ M+H ] ⁺.

Sixth step Synthesis of N- (2, 4-dimethoxybenzyl) -5- ((diphenylmethylene) amino) imidazo [1,5-a ] pyrazin-8-amine (Compound 73-8)

The flask was charged with 73-7(200mg,550.65μmol)、Int E-5(200mg,1.10mmol)、Pd₂(dba)₃(51mg,55.06μmol)、BINAP(69mg,110.13μmol)、t-BuONa(159mg,1.65mmol)、Toluene(8mL), nitrogen and reacted overnight at 100 ℃. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=40:60) and collected by spin-drying to give compound 73-8 (140 mg). MS (ESI, m/z): 464.2[ M+H ] ⁺.

Seventh step Synthesis of tert-butyl (2, 4-dimethoxybenzyl) (5- ((diphenylmethylene) amino) imidazo [1,5-a ] pyrazin-8-yl) carbamate (Compound 73-9)

73-8 (140 Mg, 302.03. Mu. Mol) and THF (5 mL) were added to the flask, dissolved, and then (Boc) ₂ O (132 mg, 604.06. Mu. Mol), DIPEA (117 mg, 906.09. Mu. Mol), DMAP (7 mg, 60.41. Mu. Mol) and nitrogen blanket were added to the flask, followed by reaction at 70℃overnight. After the completion of the reaction, the reaction mixture was diluted with water, extracted with EA (30 ml. Times.3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 73-9 (170 mg). MS (ESI, m/z): 564.2[ M+H ] ⁺.

Eighth step Synthesis of tert-butyl (5-aminoimidazo [1,5-a ] pyrazin-8-yl) (2, 4-dimethoxybenzyl) carbamate (Compound 73-10)

73-9 (170 Mg, 301.61. Mu. Mol), hydroxylamine hydrochloride (210 mg,3.02 mmol), meOH (10 mL), nitrogen blanket, 25℃were added to the flask and reacted for 3hr. After the reaction is finished, the reaction solution is directly decompressed and concentrated to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=95:5) and collected by spin-drying to give compound 73-10 (45 mg). MS (ESI, m/z): 400.2[ M+H ] ⁺.

Synthesis of ethyl 2- ((8- ((tert-butoxycarbonyl) (2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrazin-5-yl) amino) -2-oxoacetate (Compound 73-11)

73-10 (45 Mg, 112.66. Mu. Mol), DIPEA (29 mg, 225.31. Mu. Mol), THF (3 mL) and oxalyl chloride monoethyl ester (17 mg, 123.92. Mu. Mol) were added dropwise thereto, and the mixture was reacted at 25℃for 2hr under nitrogen. After the completion of the reaction, the reaction mixture was diluted with water, extracted with EA (30 ml. Times.3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 73-11 (50 mg). MS (ESI, m/z): 500.3[ M+H ] ⁺.

Tenth step Synthesis of 2- ((8- ((tert-Butoxycarbonyl) (2, 4-dimethoxybenzyl) amino) imidazo [1,5-a ] pyrazin-5-yl) amino) -2-oxoacetic acid (Compound 73-12)

73-11 (50 Mg, 100.10. Mu. Mol), liOH. H ₂O(8.40mg,200.19μmol)、THF(2mL)、H₂ O (0.5 mL), nitrogen blanket, and 25℃were added to the flask and reacted for 1hr. After the reaction was completed, the reaction mixture was adjusted to pH 4-5 with 2M hydrochloric acid, and concentrated directly under reduced pressure to give Compound 73-12 (45 mg). MS (ESI, m/z): 472.2[ M+H ] ⁺.

Eleventh step Synthesis of tert-butyl (S) - (2, 4-dimethoxybenzyl) (5- (2- (methyl (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) amino) -2-oxoacetamido) imidazo [1,5-a ] pyrazin-8-yl) carbamate (Compound 73-13)

73-12 (47 Mg, 99.69. Mu. Mol), int G (25 mg, 99.69. Mu. Mol), HATU (45 mg, 119.63. Mu. Mol) and NMP (2 mL) were added to the flask, dissolved with stirring, and then DIPEA (19 mg, 149.53. Mu. Mol) was added thereto, and the mixture was reacted at 25℃for 3hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) and collected by spin-drying to give compound 73-13 (20 mg). MS (ESI, m/z): 671.3[ M+H ] ⁺.

Twelfth step Synthesis of (S) -N ¹ - (8-aminoimidazo [1,5-a ] pyrazin-5-yl) -N ² -methyl-N ² - (6- (trifluoromethyl) -2, 3-dihydrobenzofuran-3-yl) oxamide (Compound 73)

73-13 (20 Mg, 29.82. Mu. Mol), DCM (1 mL), TFA (2 mL), nitrogen blanket, 25℃for 2hr. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure at room temperature, diluted with saturated sodium bicarbonate solution, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC and lyophilized to give compound 73 (3 mg). MS (ESI, m/z): 421.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO)δ8.28-8.04(m,1H),7.83-7.80(m,1H),7.71-7.53(m,1H),7.40-6.97(m,6H),6.33-6.01(m,1H),4.86-4.66(m,2H),2.83-2.59(m,3H).

Example 74 (S) -N ¹ - (8-Aminoimidazo [1,5-a ] pyrazin-5-yl) -N ² -methyl-N ² - (7- (trifluoromethyl) isochroman-4-yl) oxamide

First step Synthesis of 5-bromo-N- (2, 4-dimethoxybenzyl) -N- (4-methoxybenzyl) imidazo [1,5-a ] pyrazin-8-amine (Compound 74-1)

73-7 (150 Mg, 412.99. Mu. Mol) and DMF (3 mL) were added to the flask, cooled in an ice-water bath, naH (25 mg, 619.48. Mu. Mol) was slowly added, and after the addition was completed, the ice-water bath was kept for reaction for 20min, 73-2 (78 mg, 495.58. Mu. Mol) was added, and the mixture was reacted at 0℃for 2hr under nitrogen. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=35:65) and collected by spin-drying to give compound 74-1 (110 mg). MS (ESI, m/z): 483.1[ M+H ] ⁺.

Second step Synthesis of N- (2, 4-dimethoxybenzyl) -5- ((diphenylmethylene) amino) -N- (4-methoxybenzyl) imidazo [1,5-a ] pyrazin-8-amine (Compound 74-2)

The flask was purged with 74-1(300mg,825.97μmol)、Int E-5(300mg,1.65mmol)、Pd₂(dba)₃(76mg,82.60μmol)、BINAP(103mg,165.19μmol)、t-BuONa(238mg,2.48mmol)、Toluene(10mL), nitrogen and reacted at 100℃for 16hr. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase EA: pe=50:50) to give compound 74-2 (160 mg). MS (ESI, m/z): 584.3[ M+H ] ⁺.

Third step, synthesis of N ⁸ - (2, 4-dimethoxybenzyl) -N ⁸ - (4-methoxybenzyl) imidazo [1,5-a ] pyrazine-5, 8-diamine (Compound 74-3)

To the flask was added 74-2 (200 mg, 342.65. Mu. Mol), hydroxylamine hydrochloride (238 mg,3.43 mmol), meOH (5 mL), and the mixture was reacted at 25℃for 3hr under nitrogen. After the reaction is finished, the reaction solution is directly decompressed and concentrated to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=95:5) and collected by spin-drying to give compound 74-3 (60 mg). MS (ESI, m/z): 420.2[ M+H ] ⁺.

Fourth step Synthesis of ethyl 2- ((8- ((2, 4-dimethoxybenzyl) (4-methoxybenzyl) amino) imidazo [1,5-a ] pyrazin-5-yl) amino) -2-oxoacetate (Compound 74-4)

To the flask were added 74-3 (60 mg, 143.04. Mu. Mol), DIPEA (37 mg, 286.07. Mu. Mol), THF (3 mL), and then oxalyl chloride monoethyl ester (22 mg, 157.34. Mu. Mol) was added dropwise thereto, followed by a nitrogen protection and a reaction at 25℃for 2hr. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) and collected by spin-drying to give compound 74-4 (30 mg). MS (ESI, m/z): 520.2[ M+H ] ⁺.

Fifth step Synthesis of 2- ((8- ((2, 4-dimethoxybenzyl) (4-methoxybenzyl) amino) imidazo [1,5-a ] pyrazin-5-yl) amino) -2-oxoacetic acid (Compound 74-5)

74-4 (30 Mg, 57.74. Mu. Mol), liOH. H ₂O(5mg,115.49μmol)、THF(1.5mL)、H₂ O (0.5 mL), nitrogen blanket, 25℃were added to the flask and reacted for 1hr. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 2M hydrochloric acid, and the reaction solution was directly concentrated under reduced pressure to give compound 74-5 (25 mg). MS (ESI, m/z): 492.1[ M+H ] ⁺.

Sixth step Synthesis of (S) -N ¹ - (8- ((2, 4-dimethoxybenzyl) (4-methoxybenzyl) amino) imidazo [1,5-a ] pyrazin-5-yl) -N ² -methyl-N ² - (7- (trifluoromethyl)) isochroman-4-yl) oxamide (Compound 74-6)

To the flask, 75-9 (14 mg, 61.04. Mu. Mol), 74-5 (30 mg, 61.04. Mu. Mol), NMP (2 mL) and DIPEA (11.83 mg, 91.56. Mu. Mol) were added and dissolved with stirring, and HATU (28 mg, 73.25. Mu. Mol) was added thereto, followed by a reaction at 25℃for 3hr under nitrogen atmosphere. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=97:3) to give compound 74-6 (30 mg). MS (ESI, m/z): 705.2[ M+H ] ⁺.

Seventh step Synthesis of (S) -N ¹ - (8-aminoimidazo [1,5-a ] pyrazin-5-yl) -N ² -methyl-N ² - (7- (trifluoromethyl) isochroman-4-yl) oxamide (Compound 74)

To the flask was added 74-6 (30 mg, 42.57. Mu. Mol), TFA (3 mL), and the mixture was reacted at 100℃for 12hr under nitrogen. After the reaction was completed, the reaction solution was dried by spin-drying, diluted with saturated NaHCO ₃ solution, extracted with EA (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give compound 74 (5 mg). MS (ESI, m/z): 435.2[ M+H ] ⁺.

¹H NMR(400MHz,DMSO)δ11.21-11.02(m,1H),8.13-8.10(m,IH),7.94-7.88(m,1H),7.75-7.66(m,2H),7.65-7.62(m,1H),7.54-7.43(m,2H),7.10-7.02(m,1H),5.66-5.18(m,1H),4.96-4.89(m,1H),4.77-4.69(m,1H),4.16-4.14(m,1H),4.11-4.07(m,1H),2.89-2.70(m,3H).

EXAMPLE 75 (S) -N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (7- (trifluoromethyl) isochroman-4-yl) oxamide

First step Synthesis of 2- ((allyloxy) methyl) -1-bromo-4- (trifluoromethyl) benzene (Compound 75-3)

The reaction flask was charged with compound 75-1 (900 g,3.53 mol) and 75-2 (1.28 kg,10.5 mol) and tetrabutylammonium bisulfate (178 g,529 mmol) followed by a slow addition of solid KOH (376 g,6.71 mol) under an ice bath. After the addition was completed, the temperature was naturally raised to 25 ℃ and stirred for 16 hours. TLC (PE/ea=20/1, rf=0.84) detected completion of the reaction. The reaction mixture was diluted with water (1000 mL), extracted three times with ethyl acetate (1000 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated by suction filtration, separated and purified by silica gel column chromatography (PE/ea=100/1 to 20/1), and concentrated to give compound 75-3 (1.10 kg).

¹H NMR(400MHz,CD₃OD)δ7.72-7.83(m,2H),7.49(dd,J＝8.4,1.7Hz,1H),5.88-6.09(m,1H),5.19-5.41(m,2H),4.60(s,2H),4.14-4.16(m,2H).

Second step Synthesis of 4-methylene-7- (trifluoromethyl) isochroman (Compound 75-4)

Compound 75-3 (250 g,847 mmol) was dissolved in DMF (1.50L) and PPh ₃ (33.3 g,127 mmol) and Cs ₂CO₃ (331 g,1.02 mol) were added. After stirring well, pd (OAc) ₂ (9.51 g,42.3 mmol) was added under nitrogen. The reaction was warmed to 90 ℃ and stirred for 16hrs. TLC (PE/ea=20/1, rf=0.62) detected completion of the reaction. The reaction solution was diluted with water (500 mL), extracted with ethyl acetate (500 ml×3), the organic phases were combined, washed with saturated aqueous NaCl (500 ml×3), and after the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and concentrated. Purification by silica gel column chromatography (PE/ea=100/1 to 20/1) and concentration gave compound 75-4 (60.0 g).

¹H NMR(400MHz,CD₃OD)δ7.91(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,1H),7.42(s,1H),5.81(s,1H),5.18(s,1H),4.83(s,2H),4.46(s,2H).

Third step Synthesis of 7- (trifluoromethyl) isochroman-4-one (Compound 75-5)

Compound 75-4 (323 g,1.51 mol) was dissolved in a mixed solvent of 1, 4-dioxane (1.50L) and H ₂ O (1.50L), and after stirring well at room temperature, naIO ₄ (967 g,4.52mol,250 mL) was added after cooling to 0 ℃. Stirring was continued at 0 ℃ for 0.10hr. K ₂OsO₄·2H₂ O (27.7 g,75.4 mmol) was then added. After the reaction was kept at 0℃and stirred for 0.5hr, the temperature was raised to 25℃and the reaction was continued for 12hrs. TLC (PE/ea=5/1, rf=0.48) detected completion of the reaction. The reaction mixture was filtered with suction, extracted with ethyl acetate (500 mL. Times.3), and the organic phases were combined and washed with saturated NaCl (500 mL. Times.3). The organic phase was collected, dried over anhydrous Na ₂SO₄, filtered with suction, and concentrated. Purification by silica gel column chromatography (PE/ea=100/1 to 5/1) and concentration gave compound 75-5 (250 g). MS (ESI, m/z): 216.9[ M+H ] ⁺.

¹H NMR(400MHz,CD₃OD)δ8.14(d,J=8.0Hz,1H),7.67-7.79(m,2H),4.98(s,2H),4.41(s,2H)。

Fourth step (R, Z) -2-methyl-N- (7- (trifluoromethyl) isochroman-4-ylidene) propane-2-sulfinamide (Compound 75-6)

Compound 75-5 (176 g,814.23 mmol) and compound Int B-2 (256 g,2.44 mol) were dissolved in DCE (1.20L), then Ti (O ⁱPr)₄ (1.16 kg,4.07mol, 1.20L)) was added and the reaction warmed to 50℃with continued stirring 16hrs. LCMS detection was successful, without further purification, and concentrated directly to give compound 75-6 (260 g,814 mmol). MS (ESI, m/z): 320.1[ M+H ] ⁺.

Fifth step Synthesis of (R) -2-methyl-N- ((S) -7- (trifluoromethyl) isochroman-4-yl) propane-2-sulfinamide (Compound 75-7)

Compound 75-6 (260 g,814 mmol) was dissolved in THF (1200 mL), nitrogen was replaced and cooled to 0deg.C, and NaBH ₄ (154 g,2.44 mol) was added in portions. After the addition was complete, the reaction was kept at 25 ℃ with stirring for 2hrs. TLC (EA/dcm=1/10, rf=0.46) detected completion of the reaction. After cooling to 0 ℃, saturated aqueous NaHCO ₃ was added to the reaction solution to quench the reaction, after adding ethyl acetate, stirring was continued for 10min, suction filtration was performed, and the filtrate was diluted with water (1500 mL) and then extracted with ethyl acetate (500 mL x 3). The organic phases were combined and dried over anhydrous Na ₂SO₄, filtered off with suction and concentrated. Purification by silica gel column chromatography 0 PE/ea=100/1 to 10/1 and concentration gave compound 75-7 (219 g,681 mmol). MS (ESI, m/z): 321.9[ M+H ] ⁺.

¹H NMR(400MHz,CD₃OD)δ7.80(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.40(s,1H),4.88(s,1H),4.75-4.80(m,1H),4.51(d,J＝4.4Hz,1H),4.02(dd,J＝11.6,4.6Hz,1H),3.87(dd,J＝11.6,6.1Hz,1H),1.24(s,9H).

Sixth step Synthesis of (R) -N, 2-dimethyl-N- ((S) -7- (trifluoromethyl) isochroman-4-yl) propane-2-sulfinamide (Compound 75-8)

Compound 75-7 (219 g,681 mmol) was dissolved in THF (1700 mL) and NaH (40.9 g,1.02 mol) was slowly added under ice-bath. After the addition was complete, stirring was continued at 0 ℃ for 0.5hr. Then MeI (111 g,784mmol,48.8 mL) was added and the reaction was warmed to 25℃and stirred for 16hrs. After completion of LCMS detection, the reaction was quenched with water (1000 mL) and then extracted with ethyl acetate (500 mL x 3), the organic phase was dried over anhydrous Na ₂SO₄, filtered off with suction and concentrated to give compound 75-8 (228 g). MS (ESI, m/z): 335.9[ M+H ] ⁺.

¹H NMR(400MHz,CD₃OD)δ7.62-7.68(m,1H),7.55-7.59(m,1H),7.45(s,1H),4.88(br s,1H),4.69-4.76(m,1H),4.59-4.66(m,1H),4.09-4.15(m,1H),4.01-4.08(m,1H),2.50(s,3H),1.23(s,9H).

Seventh step (S) -N-methyl-7- (trifluoromethyl) isochroman-4-amine (Compound 75-9)

Compound 75-8 (228 g,680 mmol) was dissolved in CH ₂Cl₂ (500 mL) and a 2M solution of 1, 4-dioxane hydrochloride (500 mL) was added under nitrogen. The reaction solution was stirred at 25 ℃ for 1hr. LCMS detected completion of reaction, TLC (CH ₂Cl₂/meoh=10/1, rf=0.45). The reaction mixture was concentrated, diluted with water (500 mL), and extracted with ethyl acetate (500 mL. Times.3). After the aqueous phase was adjusted to pH 9-10 with NaHCO ₃ solution, extracted with ethyl acetate (500 mL. Times.3), the organic phases were combined, dried over anhydrous Na ₂SO₄, filtered with suction, and concentrated. SFC (chiral column: DAICEL CHIRALPAK IG (250 mm. Times.50 mm,10 um); mobile phase: [ n-hexane-ethanol (0.1% IPAm) ];% B: 7%) was isolated and concentrated to give compound 75-9 (38.0 g,164 mmol). MS (ESI, m/z): 231.8[ M+H ] ⁺.

¹H NMR(400MHz,CD₃OD)δ7.48-7.59(m,2H),7.41(s,1H),4.91(s,1H),4.70-4.79(m,1H),4.18(dd,J＝11.6,2.6Hz,1H),3.83(dd,J＝11.6,3.0Hz,1H),3.61(s,1H),2.44(s,3H).

Eighth step (S) -Synthesis of N ¹ - (7- ((2, 4-dimethoxybenzyl) amino) -1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (7- (trifluoromethyl) isochroman-4-yl) oxamide (Compound 75-10)

To the flask were added Int E (1.23 g,3.18 mmol) and NMP (35 mL), and after stirring to dissolve, nitrogen was bubbled for 5min, then 75-9 (700 mg,3.03 mmol), DIPEA (587 mg,4.54 mmol), HATU (1.38 g,3.63 mmol) and nitrogen blanket were added in sequence and reacted at 25℃for 2hr. After the reaction was completed, the reaction mixture was diluted with water, extracted with ethyl acetate (60 ml×3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (mobile phase DCM: meoh=98:2) to give compound 75-10 (1.8 g). MS (ESI, m/z): 599.3[ M+H ] ⁺.

Synthesis of (S) -N ¹ - (7-amino-1-methyl-1H-pyrazolo [3,4-c ] pyridin-4-yl) -N ² -methyl-N ² - (7- (trifluoromethyl) isochroman-4-yl) oxamide (Compound 75)

To the flask was added 75-10 (2.05 g,3.42 mmol), TFA (10 mL), DCM (25 mL), nitrogen blanket, and the reaction was performed at 25℃for 3hr. After the reaction was completed, the reaction solution was dried by spin-drying, diluted with saturated NaHCO ₃ solution, extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by Pre-HPLC to give compound 75.MS (ESI, m/z): 449.1[ M+H ] ⁺.

1H NMR(400MHz,DMSO-d₆)δ10.91-10.70(m,1H),8.14-7.49(m,5H),6.34(s,2H),5.66-4.97(m,1H),4.95-4.66(m,2H),4.30-4.26(m,3H),4.17-4.04(m,2H),2.83-2.65(m,3H).

Separation method

The compounds in the examples were purified by Prep-HPLC using Aglient type 1260 or Waters 2489 type HPLC, the separation column type Waters SunFire Prep C₁₈OBD(19mm×150mm×5.0μm)、Waters Xbridge Prep C₁₈OBD(19mm×150mm×5.0μm) or YMC Actus Triart C ₁₈ (20 mm. Times.150 mm. Times.5.0 μm), the column temperature 25℃and the detection wavelength 214nm, 254nm or 280nm, acetonitrile as mobile phase A, 0.05% aqueous formic acid solution or 0.05% aqueous ammonium bicarbonate solution or 0.05% aqueous TFA as mobile phase B, the volume ratio of the mobile phase being adjusted according to the polarity of the compound, and the mobile phase flow rate being 28mL/min.

Biological evaluation

Experimental example 1 test of the inhibitory Effect of Compounds on PRMT5-MTA methyltransferase Activity

Experimental method one, after pre-incubating the prepared Protein solution (PRMT 5/MEP50 (Reaction) and MTA (MCE) mixed solution) with test compounds (1000 nM start, 5-fold dilution, 7 points) at 25 ℃ for 30min, adding the prepared substrate solution (Biotinylated histone H. Sup. Peptide (Sangon)), incubating at 25 ℃ for 90min, and after the Reaction, adding the prepared detection reagent mixed solution (Protein A-Eu (Cisbio), anti-Histone H. Sup. 4 antibody (Abcam) and strepitavidin-D2 (Cisbio)) at 25 ℃ for 60min, and detecting the fluorescence signal Ratio (Ratio) by using a BMG enzyme-labeled instrument.

The percent inhibition of compounds at different concentrations was calculated as follows using the solvent set (DMSO) as negative control and the reaction buffer set (without prmt5. Mtase) as blank:

Percentage inhibition = (negative control Ratio-compound Ratio)/(negative control Ratio-blank Ratio) ×100%;

The detected signal values were fitted using the "log (inhibitor) vs. response-Variable slope" four parameter equation y=bottom+ (Top-Bottom)/(1+10 ((LogIC ₅₀ -X) × Hillslope)) in GRAPHPAD PRISM 8 to calculate IC ₅₀ values. Wherein Y is the relative inhibition activity percentage, top and Bottom are the maximum and minimum of the fitted curve, respectively, X is the logarithmic concentration of the compound, hillslope is the slope of the curve. The inhibition of PRMT5-MTA methyltransferase by the compounds was determined as described above and the results are shown in Table 1.

TABLE 1 inhibitory Activity of the compounds of the invention on PRMT5-MTA

Experimental methods II the inhibition of PRMT5-MTA methyltransferase activity by the compounds of the present invention was determined according to the instructions of the PRMT5TR-FRET kit (BPS Bioscience). PRMT5/MEP50 enzyme (BPS Bioscience) and MTA (Pichia) mixtures were pre-incubated with test compounds (100 nM, 20nM, 4 nM) at different concentrations for 30min at 25℃and then incubated with Biotinylated histone H4 peptide (BPS Bioscience)/S-adenosylmethionine (BPS Bioscience) mixed working solution at 25℃for 120min, eu-labeled antibody (BPS Bioscience) working solution was added, shaking slowly at 25℃for 30min, dye-labeled acceptor (BPS Bioscience) working solution was added, shaking slowly at 25℃for 30min, and fluorescence signal Ratio (Ratio) was detected by the microplate reader.

The percent inhibition of compounds at different concentrations was calculated using vehicle (DMSO) as negative control, buffer (without prmt5. Mtase) as blank according to the following formula:

When the percent inhibition is between 30-80%, the half inhibition concentration (IC ₅₀) or range of compounds is calculated according to the following formula:

IC ₅₀ = X (1-percent inhibition (%))/percent inhibition (%), where X is the test concentration of the compound at an inhibition between 30-80%. The inhibition of PRMT5-MTA by the compounds was determined as described above and the results are shown in Table 2.

TABLE 2 inhibitory Activity of the compounds of the invention on PRMT5-MTA

Experimental results show that the compound has a strong inhibition effect on PRMT5-MTA enzyme.

Experimental example 2 Compound pair MTAP DELETED/PARENTAL HCT cell proliferation inhibition test

The inhibition of cancer cell proliferation by the compounds of the present invention was further evaluated by testing their effect on cancer cell growth.

Experimental methods one of the experimental examples used MTAP DELETED/PARENTAL HCT116 cells from Pharmaron Inc.

MTAP DELETED/PARENTAL HCT116 cells were grown in vitro in monolayer at 37℃in MCCOYS A medium (Invitrogen) with 10% FBS+1% P/S, 5% CO ₂. Cells in logarithmic growth phase were digested and concentration was adjusted, 150 cells per well were inoculated in 384 well plates for overnight incubation, pre-diluted compounds (10000 nM start, 4-fold dilution, 10-or 5000nM start, 5-fold dilution, 8-fold) were added, DMSO was added to the negative control, DMSO was added to the blank control, and after 10 days incubation in 37 ℃ 5% CO ₂ incubator, 40 μ L CELLTITER-Glo (Promega) was added per well, and the relative chemiluminescent unit values were read in the microplate reader chemiluminescent detection mode.

The percent inhibition of compounds at different concentrations was calculated according to the following formula:

Percentage inhibition = (1- (chemiluminescent signal value of test compound-chemiluminescent signal value of control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of control)) ×100%

The percent inhibition of compounds at different concentrations was plotted against compound concentration, and IC ₅₀ values were calculated by fitting a curve according to a four parameter model by the following formula:

y=min+ (Max-Min)/(1+ (x/IC ₅₀)/(Hillslope)), where y is the percent inhibition, max and Min are the maximum and minimum values, respectively, of the fitted curve, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

The proliferation inhibitory activity of the compounds against MTAP DELETED/PARENTAL HCT116 cells was measured as described above, and the results are shown in Table 3.

TABLE 3 proliferation inhibitory Activity of the inventive Compounds against MTAP DELETED/PARENTAL HCT cells

In the second experimental example, MTAP DELETED/PARENTAL HCT116 cells were selected and purchased from HORIZON.

MTAP DELETED/PARENTAL HCT116 cells were grown in vitro in monolayer in RPMI6140 medium (source culture) with 10% FBS+1% P/S, 37℃and 5% CO ₂. Cells in logarithmic growth phase were digested and concentration was adjusted, 250 cells per well were inoculated in 96-well plates for overnight incubation, pre-diluted compound (5000 nM start, 4-fold dilution, 9 spots) was added, DMSO was added to negative control, culture medium was added to blank control, and after 7 days incubation in 37 ℃ 5% CO ₂ incubator, 50 μ L CELLTITER-Glo (Promega) was added per well for 10 minutes at room temperature and light-shielding for lysis, and the test solution was transferred to 96-well opaque white plates, and then the relative chemiluminescent unit values were read in the microplate reader chemiluminescent detection mode.

The proliferation inhibitory activity of the compounds against MTAP DELETED/PARENTAL HCT116 cells was measured as described above, and the results are shown in Table 4.

TABLE 4 proliferation inhibitory Activity of the inventive Compounds against MTAP DELETED/PARENTAL HCT cells

Experimental results show that the compound has a strong inhibition effect on MTAP DELETED HCT116 cells and has a certain selectivity on MTAP PARENTAL HCT116 cells.

Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims

A compound having a structure of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof:

in:

Ring A is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

Ring B is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C _6-10 aromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

R ¹ is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, _3-8 membered heterocyclyl, C _6-10 aromatic ring and 5-10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C substituted with _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ² is LR ² ';

L is independently a direct bond or -(CR ⁵ R ⁶ ) _p - at each occurrence;

R ² 'at each occurrence is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkyloxy, C _6-10 aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C substituted with C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

^R3 is selected from H, OH, ^halogen , CN, ^NR10R11 , _C1-6 alkyl, _C1-6 alkoxy, _C2-6 heteroalkyl, _C3-8 cycloalkyl and 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more halogen, OH, CN, ^-NR7R8 , _C1-4 ^alkyl , _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy and _C3-6 heterocyclyl;

^R4 is independently selected at each occurrence from H, OH, oxo, halogen, _CN , -NO2, _-SF5 , ^-NR7R8 , ^{-NHCOC1-6alkyl} , _C1-6alkyl , _-C2-6alkenyl , -C2-6alkynyl, _{C1-6haloalkyl} , _C1-6alkoxy , _{C2-6heteroalkyl} , _{C1-6haloalkoxy} , C3-8cycloalkyl, _3-8 membered heterocyclyl, _{C3-8cycloalkyloxy} , _C6-10aryl and _5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, _heteroalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, CN, ^-NR5R6 , ^C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy , _{C1-4haloalkoxy} _, C substituted with _{C 3-6} cycloalkyl, C _3-8 cycloalkoxy, or 3-6 membered heterocyclic group;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 3-10 membered heterocyclic group;

R ⁹ is independently selected at each occurrence from H, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl;

^R5 and ^R6 are each independently selected from H, OH, halogen, _C1-6 alkyl, _C1-6 alkoxy and _C3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, CN, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, C3-8 cycloalkyloxy, _3-6 membered heterocyclyl; or

^R5 and ^R6, together with the carbon atom to which they are attached, form a _C3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is optionally substituted by one or more OH, ^halogen , CN, ^-NR5R6 , _C1-4 alkyl group, _C1-4 haloalkyl group, _C1-4 alkoxy group, _C1-4 haloalkoxy group, _C3-6 cycloalkyl group, _C3-8 cycloalkoxy group or a 3-6 membered heterocyclyl group;

^R7 , ^R8 , ^R10 and ^R11 are each independently selected from H, _C1-6 alkyl, _-C2-6 alkenyl, _-C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, ^heteroaryl are optionally substituted with one or more halogen, CN, ^-NR5R6 , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy, 3-6 membered heterocyclyl; or

^R7 and ^R8 , ^R10 and ^R11 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, which is optionally substituted with one or more halogen, CN, ^-NR5R6 , _C1-4 ^alkyl , _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkoxy, or a 3-6 membered heterocyclic group;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

Ring A is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a benzo 3-8 membered cycloalkyl group, a benzo 3-8 membered heterocyclyl group, a 5-6 membered heteroaryl 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl 3-8 membered heterocyclyl group, and a 3-8 membered heterocyclyl group;

Ring B is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

R ¹ is independently selected at each occurrence from H, OH, halogen, -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _1-4 hydroxyalkyl, C _3-6 cycloalkyl, C 3-6 cycloalkyloxy, _3-6 membered heterocyclyl; said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _{1-4 alkoxy, C 1-4} _haloalkoxy , C 3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl; R ¹⁰ and _R ^{R 11} is each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

L is selected from a direct bond, _-CH2- , -CH( _CH3 )-, -CH( _CH3 ) _CH2- , -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene;

R ² 'is independently selected at each occurrence from Ci _-6 alkyl, Ci _-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , Ci _-4 alkyl, Ci _-4 haloalkyl, Ci _-4 alkoxy, C substituted with _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ³ is selected from H, OH, halogen, -NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , C _1-4 alkyl and C _3-6 cycloalkyl;

R ⁴ is independently selected at each occurrence from H, oxo, OH, halogen, CN, -SF ₅ , -NR ⁷ R ⁸ , -NHCOCH ₃ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _{2-6 heteroalkyl, C 1-4} _haloalkoxy , C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy and 3-6 membered heterocyclyl;

^R9 at each occurrence is independently selected from H, _C1-4 alkyl and _C3-8 cycloalkyl.

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

Ring A is selected from C _6-15 aromatic rings and 5-15 membered heteroaromatic rings;

Preferably, Ring A is selected from a C _6-10 aromatic ring and a 5-10 membered heteroaromatic ring;

Preferably, ring A is selected from a 5-10 membered nitrogen-containing heteroaromatic ring;

Preferably, ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,

Preferably, ring A is selected from pyridyl,

Preferably, ring A is selected from

Preferably, Selected from

The wavy line It indicates the point of attachment of the group to the rest of the molecule.

The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

Ring B is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroarylphenyl and 3-8 membered heterocyclylphenyl;

Preferably, ring B is selected from a C _6-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 5-6 membered heteroarylphenyl ring and a 5-6 membered heterocyclylphenyl ring;

Preferably, ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring and a 6-membered heterocyclylphenyl group;

Preferably, ring B is selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, an indole ring, an isoindole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a quinoline ring, an isoquinoline ring, Benzopiperidine ring, benzotetrahydrofuran ring and pyridopyran ring;

Preferably, ring B is selected from a benzene ring, a pyridine ring, a pyridazine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a benzopiperidine ring, Benzotetrahydrofuran ring and pyridopyran ring;

Preferably, ring B is selected from a benzene ring,

Preferably, Selected from

The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

R ¹ is independently selected at each occurrence from H, OH, halogen, -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy and 3-8 membered heterocyclyl; said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _{1-4 alkoxy, C 1-4} _haloalkoxy , C 3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl; R ¹⁰ and _R ^{R 11} is each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

Preferably, R ¹ is independently selected from H, OH, halogen, -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C 1-6 haloalkoxy, C _1-6 hydroxyalkyl and C _3-8 cycloalkyl at each occurrence; the alkyl, alkoxy, heteroalkyl, cycloalkyl are optionally substituted with one or _more halogen, OH, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; R ¹⁰ and R ¹¹ are independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

Preferably, R ¹ is independently selected at each occurrence from H, OH, halogen, -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _3-8 cycloalkyl; R ¹⁰ and R ¹¹ are independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group;

Preferably, R ¹ at each occurrence is independently selected from H, halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , azetidinyl, pyrrolidinyl, piperidinyl, -NH ₂ , -CONH ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _3-8 cycloalkyl;

Preferably, R ¹ at each occurrence is independently selected from H, -NH ₂ , -CONH ₂ , C _1-4 alkyl and C _1-4 alkoxy;

Preferably, R ¹ at each occurrence is independently selected from H, -CH ₃ , -NH ₂ , -CONH ₂ and -OCH ₃ .

L is selected from a direct bond, -CH(C _1-6 alkyl)- and C _3-6 cycloalkyl;

Preferably, L is selected from a direct bond, _-CH2- , -CH( _CH3 )-, -CH( _CH3 ) _CH2- , -CH(cyclopropyl)-, cyclopropylene, cyclobutylene and cyclopentylene.

The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

Preferably, R ² 'is independently selected at each occurrence from C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, said alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl being optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl;

Preferably, R ² 'is independently selected at each occurrence from C _1-6 alkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl;

Preferably, R ² 'at each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH ₂ OCH ₃ , morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridyl, Optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

Preferably, R ² 'at each occurrence is independently selected from methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl, -CH ₂ OCH ₃ ,

Preferably, ^R2 at each occurrence is independently selected from methyl, isopropyl, trifluoroethyl, isobutyl,

The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

Preferably, R ³ is selected from H, OH, halogen, -NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , C _1-4 alkyl and C _3-6 cycloalkyl;

Preferably, R ³ is selected from H and C _1-4 alkyl;

Preferably, ^R3 is selected from H and methyl.

The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

R ⁴ is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR ⁷ R ⁸ , -NHCOCH ₃ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _{1-4 haloalkoxy, C 3-8} _cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy and 3-6 membered heterocyclyl;

Preferably, ^R4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, ^-NR7R8 , _C1-4 ^alkyl , _C1-4 haloalkyl, _C1-6 alkoxy, C2-6 heteroalkyl, _C1-4 haloalkoxy, _C3-8 cycloalkyl, _3-8 membered heterocyclyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more halogen, CN ^, ^-NR5R6 , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, C3-8 cycloalkyloxy and _3-6 membered heterocyclyl;

Preferably, R ⁴ is independently selected at each occurrence from H, oxo, CN, halogen, -NR ⁷ R ⁸ , C _1-4 haloalkyl, 3-8 heterocyclyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, C _{1-6 alkoxy, C 2-6} _heteroalkyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl being optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl and C _1-4 haloalkyl;

Preferably, R ⁴ is independently selected at each occurrence from H, oxo, CN, F, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , azetidinyl, pyrrolidinyl, piperidinyl, CF ₃ , C _3-8 cycloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl and 5-6 membered heteroaryl, wherein the alkoxy, heteroalkyl and heteroaryl are optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl and C _1-4 haloalkyl;

Preferably, R ⁴ at each occurrence is independently selected from H, oxo, F, -N(CH ₃ ) ₂ , CF ₃ , CN, cyclopropyl, -SF ₅ and -OCF ₃ .

The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

^R5 and ^R6 are each independently selected from H, _C1-6 alkyl, _C1-6 alkoxy and _C3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, _C1-4 alkoxy, _C3-6 cycloalkyl, 3-6 membered heterocyclyl; or ^R5 and ^R6, together with the carbon atom to which they are attached, form a _C3-6 cycloalkyl, 3-6 membered heterocyclyl, wherein the cycloalkyl, heterocyclyl is optionally substituted by one or more halogen, OH, _-NH2 , NH( _C1-4 alkyl), N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, 3-6 membered heterocyclyl;

Preferably, R ⁵ and R ⁶ are each independently selected from H, C _1-4 alkyl; or R ⁵ and R ⁶ , together with the carbon atom to which they are connected, form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group;

Alternatively, ^R3 and ^R4 together with the atoms to which they are attached form a 3-8 membered heterocyclic group.

The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

m is 0, 1 or 2.

The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

n is 0, 1 or 2.

The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

p is 1.

A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the compound is a compound of formula I-1:

Where q is 0 or 1.

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the compound is selected from:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and/or treating a disease or condition associated with PRMT5 activity;

Preferably, the disease or condition associated with PRMT5 activity is a disease that is sensitive or responsive to inhibition of PRMT5 activity;

Preferably, the disease or condition associated with PRMT5 activity is cancer or tumor, more preferably cancer or tumor with MTAP deficiency;

The cancer or tumor is preferably esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL) or lymphoma, etc.

The method for preparing the compound according to any one of claims 1 to 15, comprising the steps of:

Step 1: Compound IA-1 and R ² NH ₂ undergo reductive amination to generate compound IA-2;

Step 2: Compound IA-3 and acyl chloride Compound IA-4 is generated through condensation reaction;

Step 3: Compound IA-4 is hydrolyzed to generate compound IA-5;

Step 4: Compound IA-2 and compound IA-5 undergo condensation reaction to generate compound I;

If necessary, the fifth step is to remove the protecting group of the condensation product of the fourth step to generate compound I;

in,

Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁹ , m, n and p are as defined in any one of claims 1 to 15.